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TYPE
Original Research
PAGE NO.
6-20
10.37547/tajmspr/Volume07Issue02-02
OPEN ACCESS
SUBMITED
04 December 2024
ACCEPTED
02 January 2025
PUBLISHED
05 February 2025
VOLUME
Vol.07 Issue02 2025
CITATION
Muhammad Nouman, Faisal Humayun, Saad Ahmad khan, Abdul Qadeer
khan, Hassan Zeb, Deena Jamal, Musawir Ali, Abrar Hussain, & Faiza
Shams. (2025). Gut Microbiome-Host microRNA Interactions in Cancer
Development and Immune Regulation: A Case of Colorectal and Breast
Cancer. The American Journal of Medical Sciences and Pharmaceutical
Research, 7(02), 6
–
20.
https://doi.org/10.37547/tajmspr/Volume07Issue02-02
COPYRIGHT
© 2025 Original content from this work may be used under the terms
of the creative commons attributes 4.0 License.
Gut Microbiome-Host
microRNA Interactions in
Cancer Development and
Immune Regulation: A
Case of Colorectal and
Breast Cancer
Muhammad Nouman
M.Phil Health Biotechnology, Department of Biotechnology, Faculty of
Chemical and Life Sciences Abdul Wali Khan University Mardan, Pakistan
Faisal Humayun
Department of Biotechnology, Abdul Wali Khan University Mardan,
Pakistan
Saad Ahmad khan
Department: Biotechnology and Genetic Engineering, Hazara University
Mansehra, Pakistan
Abdul Qadeer khan
Department of Allied Health Science, Iqra National University Peshawar,
Pakistan
Hassan Zeb
Department of Allied Health Science, Iqra National University Peshawar,
Pakistan
Deena Jamal
Department of Biotechnology, Abdul Wali Khan University Mardan,
Pakistan
Musawir Ali
Department of Allied Health Science, Iqra National University Peshawar,
Pakistan
Abrar Hussain
MPhil Biotechnology & Genetic Engineering from Institute of
Biotechnology and Genetic Engineering, The University of Agriculture
Peshawar Pakistan, Pakistan
Faiza Shams
Department of Biotechnology, Faculty of Chemical and Life Sciences Abdul
Wali Khan University Mardan, Pakistan
Corresponding Author: Faiza Shams
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Abstract:
Breast and colorectal cancers represent
primary malignancies that researchers worldwide
analyze for genetic along with environmental risk
elements to build therapeutic methods for better
cancer outcomes. The most prevalent cancer in
women is breast cancer along with colorectal cancer
ranking second and third respectively among females.
Adults across the globe most often experience these
cancer types yet the present scenario shows rising
incidence rates among younger patients. These early-
onset tumors often start in the advanced stages of
their aggressive type and produce a poor clinical
outlook for patients. Past research initially
concentrated on identifying genes which might help
explain cancer origins but this approach changed in
recent years. Scientific research has demonstrated
that genetics and epigenetics together with
environmental elements strongly affect cancer
predisposition. Due to recent paradigm shifts in
scientific inquiry researchers performed diverse
investigations to analyze host microRNA response
patterns and validated microbiota-gut communication
systems which significantly influenced disease
occurrence and state. These factors directly affect the
disease's final results. Immunosuppression stands as a
major worrisome consequence among all identified
unfavorable effects of this disease because at present
such patients remain susceptible to numerous
infections.
Recent
scientific
research
found
microbiome along with microRNA to substantially
affect immunosuppression. The review tracked host
microRNA activity alongside gut microbiome changes
during disease development to determine their
influence on immunosuppression in patients.
Understanding the microRNA and microbiome
interaction mechanisms with disease presentation
effects on immune function would enable future
therapeutic development opportunities targeting host
microRNA and patient gut microbiome functions. The
combination of inhibitory-miRNA therapies with
miRNA mimic-based therapeutics and immune
checkpoint blockade therapies and bacteria-assisted
tumor-targeted therapies helps manage cancer. This
study
simultaneously
investigated
noninvasive
biomarkers that could help with both cancer diagnosis
and treatment plans and prognostic assessment.
Keywords:
Breast Cancer, Colorectal Cancer, miRNA,
microbiota, immunosuppression.
Introduction:
Breast cancer (BC) is the most frequent
malignancy among females and remains the major
cause of cancer-related mortality, with an expected
685,000 deaths recorded in 2020. Globally, roughly 2.3
million new instances of female breast cancer were
reported in 2020, representing 11.7% of all cancer cases
and accounting for nearly one in four cancer diagnoses
among women. [1,2]. Breast cancer is divided into four
molecular subtypes, which are considerably impacted
by age: luminal A (ER+ and/or PR+, HER2-), luminal B
(ER+ and/or PR+, HER2+), human epidermal growth
factor receptor 2-enriched (ER-, PR-, HER2+), and basal-
like (ER-, PR-, HER2-). These subgroups indicate
differences in incidence, therapeutic response, disease
progression, and survival outcomes. [3]. While breast
cancer risk normally increases with age, a large number
of instances are being found among younger individuals
internationally.
Although early-onset breast cancer is uncommon, it
accounts for 7% of all breast cancer cases and nearly
40% of malignancies diagnosed in women aged 15
–
39.
A positive family history of cancer is the most significant
personal risk factor, driven by a high genetic
susceptibility. Germline mutations in BRCA1 and BRCA2
are major factors, with BRCA carriers not only being at a
heightened risk of early-onset breast cancer but also
facing a 16
–
35% greater potential of getting
contralateral breast cancer. Young premenopausal
breast cancer generally manifests at advanced stages
and is associated with aggressive subtypes that have a
poor prognosis. Triple-negative (ER-, PR-, HER2-) and
HER2-positive (HER2+) breast tumours with high-grade
proliferation are particularly fatal in younger individuals.
Compared to older women, individuals with early-onset
breast cancer had shorter survival rates, contributing to
increased breast cancer mortality. Among elderly
patients, Luminal A, the least aggressive subtype with a
favorable prognosis, is widespread in those over 50,
whereas Luminal B, a more aggressive subtype with
high-grade proliferation, is often detected in persons
older than 70.
Approximately 90% of breast cancer occurrences are
random, with no clear hereditary susceptibility.
Consequently, additional variables have a substantial
role in the development of irregular breast cancers,
especially in new non-BRCA carriers without a family
history or genetic linkages. Hormonal imbalances,
obesity, and eating habits are among the primary risk
factors that greatly impact the condition. Additionally,
new research has identified the possible function of the
gut microbiome and host microRNA (miRNA), either
independently or via complicated pathways, in
contributing to BC development.
Colorectal Cancer
CRC is the 3rd most common cancer diagnosed in both
sexes, ranking as the 3rd most common in men and the
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2nd most common in females. [9]. in 2020, an
estimated 1.9 million new cases of CRC were reported,
along with approximately 935,000 deaths, accounting
for up 10% of all cancer diagnoses and deaths
worldwide. CRC incidence is growing constantly, and
especially in Asia and in the East Asian countries.
[10,11]. Especially evident is such trend in developing
countries with the average HDI; rapid social and
economic change along with acceptance of
Westernized way of life cause rising CRC prevalence
and mortality rates. Conversely, countries with a
higher HDI have witnessed the outcome of CRC
improving due to enhanced early detection strategies,
increased adoptions of polypectomy, and innovation in
the care given before and after surgery that has
resulted in decreased CRC incidence and mortality.
[12.13]. Cancer statistics in the United States show an
increased incidence of young-onset colorectal cancer
(20
–
49 years of age), which constitutes nearly 10% of
all CRC cases. Specifically, young-onset colon and rectal
cancers constitute 11% and 18%, respectively,
compared to persons aged 50 and older. [14]. In the
Asia-Pacific region, which is characterized by urbanized
lifestyles dominated by westernization and has a larger
population of young people, the incidence of young-
onset colorectal cancer is also increasing, similar to
trends in Western countries. [15]. Risk factors include
obesity, sedentary lifestyle, and diet rich in meat, high
calorie and fat, low in fiber content. [16]. Besides,
differences in aggressiveness, tumor staging, and
clinical outcomes were documented for young-onset
versus late-onset colorectal cancer patients. 17. Early
detection plays a crucial role in enhancing the
diagnosis and prognosis of CRC because it offers
adequate surgical intervention prior to the beginning
of metastases. The 5-year survival percentage for
individuals with advanced-stage IV CRC declines to
14%, whereas patients detected at an early/localized
stage had a survival rate of 90%. This significant
disparity underlines the importance of early
identification and effective surgical therapy in
improving survival results.[18].
Most CRC are irregular, constituting about 90% of all
occurrences, with no apparent family history or
genetic connection. The remaining 10% are
categorized as family, having a documented hereditary
propensity. [24]. Early-onset CRC is typically connected
with hereditary cancer syndromes, which may be
diagnosed in younger persons with a family history or
supplementary risk factors, such as inflammatory
bowel illness or genetic disorders like Lynch syndrome
or familial adenomatous polyposis. Identifying these
risk factors can lead to suggestions for preventative
interventions, including weight loss, greater physical
activity, a diet rich in vegetables, fruits, and whole
grains, avoidance of alcohol and smoking, and increased
vitamin D consumption to correct low levels. [14]. In
contrast, spontaneous CRC arises because to the
deregulation of many signaling pathways. [20].
Recognized carcinogenic mechanisms in sporadic CRC
include chromosomal instability (CIN), CpG island
methylator phenotype (CIMP), and microsatellite
instability (MSI), all of which entail somatic genetic
alterations. [21,22]. The most frequent route,
chromosomal instability (CIN), accounts for 70% of
sporadic CRC cases and occurs from the accretion of
mutations in certain oncogenes and tumor suppresser
genes, such as APC, KRAS, PIK3CA, BRAF, SMAD4, and
TP53. [23].
Recent investigations have emphasized the relationship
between host miRNA and the gut microbiota in
colorectal cancer. These variables may have a
substantial influence in CRC development, particularly
in situations where there is no apparent genetic
predisposition, and might contribute to the incidence of
irregular colorectal cancer at a younger age.
Inter-Domain Communications Between the Gut
Microbiome and Host miRNAs in Cancer Endogenous:
miRNAs function as regulatory small RNA molecules
which use 3ʹ
-untranslated region binding to control
gene expression in mRNAs. Interspecies interactions
lead to modified proteins through three molecular
pathways that involve mRNA disruption together with
translation reduction and gene functionality silencing
mechanisms. A single miRNA molecule connects to
multiple mRNAs which regulate fundamental biological
processes including cell growth and signaling and also
DNA repair procedures and cell differentiation while
mediating stress responses. [24]. The abnormal
expression of miRNAs affects gene regulation and sets
the stage for multiple diseases which include cancer.
[25]. MiRNAs linked with cancer belong to one of two
categories: oncogenic oncomiRs or tumor-suppressor
TS-miRs. Several groups of microRNAs such as oncomiRs
and TS-miRs play vital roles in cancer development as
well as tumor metastasis and treatment resistance
mechanisms. [26.27]. The field of metastasiRs
(metastasis-associated miRNAs) directs metastasis
processes whereas metastasis-suppressor miRNAs
function to impede metastatic progression. [28,29]. The
symbiotic relationship between human microbiota and
microbiome brings fundamental benefits to essential
div operations. Age together with lifestyle patterns
and nutrition factors and environmental agents and
hormone fluctuations along with presumed illnesses
and host genetic makeups contribute to shaping the
microbiota. ³⁰ Specific parts of the gut microbiota
provide beneficial functions that enable multiple host
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activities including nutrient bioconversion and harmful
microorganism defense and control of nervous system
function and metabolic response and immunological
stability. [31,32]. Gut microbiota dysbiosis describes a
state where irregular microbial gut relationships arise
leading to disruptions of typical microbial stability
patterns. The disrupted microbiome leads to negative
health effects which range from inflammatory
conditions through infectious diseases and eventually
into malignant disorders. Cancer initiation and
progression appear to be influenced by modulated
biological balance through microbiota alterations
which affect host metabolites and genes as well as
proteins expressed by hosts. [31]. When modifications
occur to the immune system, they lead to obesity
development and immune system damage. The
altered microbiota affects lipid metabolism-related
miRNA expression which results in simultaneous
obesity and cancer development. [33]
Modern research shows a strong link exists between
host miRNAs and gut microbiota. miRNAs control gene
expression through host mRNA binding but the gut
microbiota alters the expression levels of host miRNAs
through
MyD88-dependent
pathways
and
microbiologic compounds that influence gene
expression in the colon [34]. Lastly the host can modify
gut microbiota by releasing miRNAs into extracellular
vesicles which microorganisms ingest (Figure 1). The
two-way interaction between miRNAs from host cells
and gut bacteria regulates gene expression in hosts.
[35]. Studied evidence establishes that dietary
components consumed by hosts modify their miRNA
expression levels which results in modified gut
microbiota. Research has established that dietary
agents can directly change the composition of
microbiota through two key findings [36,37]. The
concurrence of microRNA expression abnormalities and
microbiota imbalance creates the foundations for
various diseases including cancer.
Host miRNAs potentially interact with gut microbiota
through expression-based communication to create
new treatment possibilities for cancer which can be
targeted via medication. The analysis of cancer
metabolism relies heavily on miRNA levels as a primary
druggable target in today's cancer research. The
development of miRNA-based therapeutic approaches
becomes
possible
through
miRNA
expression
modulation which decreases oncomiR overexpression
typical across malignancies while restoring tumor-
suppressor miRs (TS-miRs) that tumors normally
inactivate. miRNA inhibitor-based treatments lower
oncomiR levels via antagomiRs (anti-miRs) and
antisense anti-miR oligonucleotides (AMOs) and locked
nucleic acids (The therapy using synthetic TS-miR
sequences as mimics serves to reproduce endogenous
TS-miRs that Dicer and Ago2 proteins detect. [38,39].
Figure 1:
The process of communication between host
gene expression and host miRNA activity with the gut
microbiome proceeds across multiple domains ruling
gene expression through miRNA binding to correct
mRNAs and the gut microbiome alters miRNA
expression through MyD88-dependent mechanisms
and microbial metabolites. The host alters gut
microbial composition through extracellular vesicle
release of miRNAs that microbes absorb to modify their
microbiome structure.
Research on expression-based interactions between gut
microbiota and host miRNAs shows promise for
developing cancer treatment pharmacological targets.
Cancer metabolism and its associated druggable target
expression levels of miRNA stand as the primary
research focus at present. Controlling miRNA
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concentrations enables the development of miRNA-
derived
cancer
treatments
through
oncomiR
suppression and restoration of TS-miR function which
cancer cells naturally silence. Therapies that target
oncomiRs with miRNA inhibitors employ different
methods featuring locked nucleic acid (LNA)
antagomiRs
(anti-miRs)
antisense
anti-miR
oligonucleotides (AMOs) and miRNA sponge.
Therapeutic uses of miRNA mimics employ synthetic
sequences derived from TS-miRs so Dicer and Ago2
proteins can recognize them for incorporation. [38,39].
Breast cancer shows interactions between gut
microbiome and host miRNAs while miRNAs function
as stable regulatory RNAs that exist in varying amounts
within blood and plasma. A range of specific and
indicative BC-specific circulating miRNAs have been
detected for potential biomarker use in cancer
evaluations. [40]. Testing the circulation of these
miRNA biomarkers on patients with early-onset triple-
negative breast cancer (TNBC) allows researchers to
create minimal invasive and affordable novel
biomarkers to aid in clinical diagnosis. Research on
circulating miRNAs shows potential to enhance
identifying cancer indicators and predicting outcomes
in combination with treatment approaches. [41].
Tumor recurrence rates as well as overall survival and
tumor staging have been linked specifically to these
miRNA biomarkers thus making them useful
biomarkers across different cancer subtypes. Research
comparing tumor-derived miRNAs to non-tumor
samples discovered elevated expression levels of miR-
21, miR-106a, and miR-155 in tumors but simultaneous
under expression of miR-126, miR-199a, and miR-335.
Breast tumor tissue types present distinct relationships
with the quantities of expressed miRNA molecules. The
levels of expression of miR-21, miR-126, miR-155, miR-
199a, and miR-335 relate to BC clinical factors along
with histological tumor grades and sex hormone
receptor status. [42]. Blood miR-21 measurements
serve to distinguish breast cancer patients from
healthy women and identify distant metastasis from
locoregional recurrence of the disease according to
two research reports. Research shows that high miR-
21 gene expression at disease initiation directly
influences breast cancer development potential which
acts as a clear indicator at both diagnostic and
prognostic stages of cancer progression. Estimates
classify MiR-21 as an oncogene because this molecular
factor allows tumor growth rates to increase by
directing suppression against key tumor stabilizing
genes TPM1 and PDCD4. [43]
Plasma levels of miRNAs show potential as biomarkers
to identify and track cancer development early. The
study results showed elevated levels of miR-21, miR-
155, and miR-10b oncomiRs (oncogenic microRNAs) in
breast cancer patients while Let-7a tumor suppressor
miRNA levels in controls displayed decreased
expression. The treatment procedures led to elevated
levels of Let-7a and reduced concentrations of miR-21,
miR-155, and miR-10b across patient plasma. The post-
operative stages showed significant variation in levels of
miR155 relative to the pre-operative stages which
supports its potential as a biomarker and response
indicator for Luminal A subtype treatment. [44]. Current
research demonstrates a dual biomarker approach
using miR-195 and miR-331 expression to separate
metastatic from locally limited luminal A breast cancers.
A definitive distinction between luminal A and luminal B
centers on miRNA cluster miR99a/let-7c/miR-125b
elevation that prolongs the survival period for patients
with luminal A cancer but only provides good clinical
outcomes with high levels of miR-99a expression. This
miRNA cluster functions as both a biomarker to separate
luminal A from B while serving as a prognostic tool
within luminal A for patients demonstrating low miRNA
levels that indicate poor survival rates. [45]. Luminal B
subtype pre-operative patients present elevated blood
levels of miR-195 suitable for early diagnosis. Multiple
miRNAs demonstrated tumor-suppressive effects
against HER2 augmented EGFR1 pathway dynamics thus
restraining cancer cell proliferation including miR-147
with miR-124 also revealing tumor-suppressive
properties alongside miR-193-3p. The expression of
miR-342-5p and miR-744 declines in HER2-positive BC
tumors in comparison to HER2-negative breast cancers.
The miRNAs Let-7f, Let-7g, miR-107, miR-10b, miR-126,
miR-154, and miR-195 serve as specific biomarkers for
HER2-positive breast cancer. Furthermore, miR-4734
and miR-150-5p demonstrate potential for use as
predictive biomarkers. [46]. According to Zeng et al the
diagnostic biomarker potential of miR-30a in plasma
improves detection precision compared to conventional
tests including cancerous embryonic antigen and cancer
antigen 15-3 (CA15-3) through its reduced levels in BC
patients. The levels of miR-30a provide major insights
into the diagnosis of breast tumors with either ER or
triple-negative features. Furthermore, some studies
done on the behavior of miRNA were identified that
miR-155 as a potential prognostic biomarker in TNBC
patients, where elevated levels of miR-155 showed a
protective action by reducing RAD51 expression and
improving better clinical outcome for IR-based
therapies in TNBC patients.43,58 Whereas miR-18b,
miR-103, miR-107, and miR-652 levels interact with
recurrence and deprived survival in TNBC.59 In addition,
miR-376c, miR-155 and miR-17 are exposed as
biomarkers in the early-stage, whereas miR-10b is a
late- stage biomarker in TNBC,60 while up-regulated
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miR- 532-5p might be employed as a possible
biomarker for prognosis. [47]
Research demonstrates that TNBC types with poor
prognoses show increased levels of miR-138 which
demonstrates this protein's usage possibilities for both
diagnostic testing and health condition assessments.
Research shows miR-374 produces bigger tumors
while miR-105 and miR-93-3p at elevated levels lead to
poor patient survival. TNBC patients who develop
chemoresistance show abnormal patterns of several
specific miRNAs in their tissue samples. Resistance to
chemotherapy and poor radiation response appear
through low miR-200c levels while increased miR-181a
expression associates with non-responsive neo-
adjuvant chemotherapy treatment. [48] Numerous
studies show how miRNA signatures support
diagnostic and predictive and prognostic applications
as biomarkers for cancer types especially TNBC
specifically when occurring in people with early disease
onset. [49]. Breast cancer studies Investigated
Oncogenic microRNAs which drive breast cancer
invasion and facilitate metastasis and cell migration
during
cancer
growth
and
proliferation.65
Predominantly
predictive
microRNA
markers
associated with hormone therapy and targeted
therapy and radiotherapy and chemotherapeutic
agents and positive and negative prognostic markers,
and diagnostic markers to identify early BC cases and
BC molecular subtypes and histological subtypes, have
been characterized.
Medical research into breast cancer microbiome
relationships discovered that the microbiome
signature of ER-positive and HER2-positive breast
cancer tissues overlapped but triple-negative and
triple-positive
samples
exhibited
mismatched
microbial patterns. Research data enables clinicians to
create diagnostic tools while offering therapies for
different cancer treatments. [50] Studies indicated
that triple-negative breast cancer contained lowest
microbial diversification while the ER-positive subtype
displayed maximum diversity. Various bacterial genes
present in the gut microbiome produce enzymes which
break down estrogen. Endogenous estrogen combined
with corresponding metabolic changes directly
correlate with breast cancer risk rates in women who
have
ceased
menstruating.
Research
shows
endogenous estrogen plays a leading role in breast
cancers because 70% of tumors in postmenopausal
patients test positive for this receptor. [51] Thus,
circulating estrogen and its metabolites modify the
efficacy of the gut microbiome against breast
cancer.71 Postmenopausal women have microbiota
composition different from those of premenopausal
women, creating different metabolites. In addition to
that,
during
the
postmenopausal
period,
microorganisms that had a synergistic effect during
premenopausal would compete with each other. Zhao
et al. mentioned that premenopausal women have
higher abundances of Bacteroidetes and Roseburia spp.
but
lower
abundances
of
Firmicutes
and
Parabacteroides. On the other hand, postmenopausal
subjects had a lower Firmicutes to Bacteroidetes ratio,
along with higher Escherichia coli and Bacteroides
compared to premenopausal women. [52] Changes in
endogenous estrogen concentration and composition of
the gut microbiome differ between premenopausal and
postmenopausal women, and this disequilibrium may
promote breast cancer in postmenopausal via higher
circulating estrogen levels. These roles of the microbiota
in the initiation and progression of breast carcinomas
could lead to new therapeutics in the future.
Furthermore, it has been shown that the gut
microbiome composition of BC women differs based on
div mass, with obese BC women showing lower
amounts of Firmicutes, Faecalibacterium prausnitzii,
and Blautia sp. than normal-weight patients. It is also
noted that the presence of some bacterial groups, such
as the Clostridium leptum cluster, the Clostridium
coccoides cluster, Faecalibacterium prausnitzii, and
Blautia sp, correlates with the clinical stage; BC patients
at stages II/III show a higher density of such bacteria
than patients with stage 0/I. [53].
Besides the gut microbiome, a study on the mammary
microbiome showed that the bacterial groups present in
mammary tissue are not different from the surrounding
normal tissue or tumours tissue. however, Escherichia
coli's high profusion in BC patients relative to healthy
controls indicated that it was promoting cancer. Several
potential pathways through which microbes may
influence the development of BC have been identified.
These are metabolism function, DNA damage, genomic
stability, and the regulation of chronic inflammation and
immunology. Most microbiome detection research has
instead depended on the sequencing method of a
particular section of the bacterial 16S rRNA gene. Many
studies based their work on qPCR or a DNA array, but
other techniques have recently gained popularity:
Breast cancer can result from the gut circulation of
microbial and digestive materials because these
substances disrupt numerous pathways that affect the
host's gene expression or signal transduction. [54]
Moreover, the host's food and lifestyle modify the gut
microbiota population. If the diet has a negative impact
on the composition of the microbiota, then it may
rapidly drive malignancy development, even breast
cancer. Various microbiota in the gut will cause an
imbalance between various phylae, and the type of
dietary fiber (soluble and insoluble) absorbed will affect
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this. Probiotics and a well-balanced diet can help to
improve the potential dysbiosis between Firmicutes
and Bacteroidetes that may come up in the context of
breast cancer. Triple-negative breast carcinoma, which
presents more frequently in young breast cancer
patients, is the most aggressive type of BC. Endocrine
treatments and HER2-targeted drugs fail in TNBC, and
chemoresistance
typically
develops
after
chemotherapy. Therefore, finding effective targeted
therapies for TNBC based on modifying miRNA levels
and/or microbiota status is expected to improve
prognosis [55]
Interaction of Gut Microbiome and Host miRNAs in
Colorectal Cancer
Many miRNAs are identified having potential biological
and clinical implications in CRC. Aberrant miRNA
expression is related to the disease course, prognosis,
and survival of colorectal cancer. Differential
expressions of miRNA have been reported between
colorectal cancer tissue and normal colorectal
epithelium; therefore, specific miRNAs enhance
prognostic and predictive power as biomarkers in
colorectal cancer. Where such miRNAs can predict the
fate of the disease, as well as the reactions to
chemotherapy and radio treatment in patients.
Dysregulation of miRNA, would modify its role in
numerous cellular pathways leading to cell
proliferation,
differentiation,
apoptosis,
and
developme
nt, such as WNT/β
-catenin route, EGFR
pathway, TGF-
β signaling system, and epithelial
-to-
mesenchymal transition. [56] Thus, identification of
participation of miRNAs in the above-mentioned
pathways will benefit the selection of CRC potential
biomarkers and therapeutic strategies.
miRNA expression alterations in various phases of CRC,
where a few of them express only in the late phase of
CRC, such as miR-141, which is identified as a
differential diagnostic biomarker and higher amounts
of miR-141 in plasma are associated with poor survival
of CRC patients.85 On the other hand, serum miR-21
has been identified as a potential marker for the early
diagnosis and prediction of CRC. miR-21 is
overexpressed in various cancers, such as colorectal
cancer, which makes it a potential diagnostic
biomarker for CRC.86 miR-21 expression is associated
with TNM stage where higher miRNA expression is
observed at
later
stages
of
CRC.
[55-56]
Overexpression of miR-21 enhances the tumor
progression associated with poor survival and
sensitivity to chemotherapy in patients. It functions as
an oncogenic miRNA (oncomiR) that could modulate
the expression levels of several cancer- associated
genes, PTEN, TPM1, and PDCD.88 Besides, miRNA
signatures could be used as diagnostic, predictive, and
prognostic biomarkers for CRC. miR-31 is linked with
BRAF mutation in CRCs, in which it is strongly correlated
with aggressive phenotype, showing poor prognosis in
patients, which implied that higher expression of miR-
31 is related with BRAF V600E mutation in stage IV CRC
patients. Moreover, a significant correlation of elevated
expression level of miR-31 has been associated with
poor survival. Besides, a significantly high elevation of
expressions of miR-21 and 31 may also be seen in even
precancerous colorectal adenoma, which may be
targeted as a biomarker for screening CRC.[57].
Alternatively, host miRNA may influence the size and
composition of bacteria in the gut microbiome of an
individual. The researchers have conducted a number of
studies which explored the association of miRNA
expression with the microbiota in human CRC tumors
and normal tissues.[34] Using modern technologies
including metagenomic sequencing, research has
revealed the gut microbiome association with the
mechanisms of colorectal carcinogenesis, by the
presence of a variety of microorganisms such as
Fusobacterium nucleatum, Pepto-streptococcus stoma
tis, and Parvimonasmicra, towards the development of
CRC. Such susceptibility and development of CRC can be
controlled by the makeup of the gut micro biome by
controlling such processes as inflammation and DNA
damage in the host by producing chemicals that either
generate or inhibit tumors. Gut bacteria are present in
varied locations, including the ascending colon, distal
colon, proximal ileum, and jejunum within the intestine,
where they play crucial functions, such as the
production of vitamins and degradation of food
chemicals. [57] Of several phyla of bacterial species
isolated in the microbiome, the Firmicutes, and
Bacteroidetes were shown to be highly abundant in the
gut.
Such overabundance of
Firmicutes
and
Bacteroidetes and Proteobacteria were associated with
differently expressed miRNA in colorectal cancer. Some
studies have demonstrated that Bacteroidetes and
Firmicutes phyla are highly associated with the levels of
miR-141-3p, whereas Actinobacteria, Bacteroidetes,
Cyanobacteria, and Firmicutes are associated with the
levels of miR-200a-3p.
Dysbiosis/imbalance of the microbial community in the
gut is associated with the development of CRC. CRC
patients show to have an enrichment of many enteric
bacteria such as Fusobacterium nucleatum, Bacteroides
fragilis, Escherichia coli, and Enterococcus faecalis
whereas a decreased number of microorganisms
including
Faecalibacterium,
Blautia, Clostridium,
Bifidobacterium, and Roseburia sp.[58] Such dysbiotic
pattern revealed in gut microbiome in CRC patients
from apparently healthy individuals that tends to enrich
the opportunistic pathogen bacteria with detrimental
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pro-inflammatory impact while reducing commensal
bacteria population like the butyrate-producing
bacteria. Butyrate-producing microorganisms are
associated with protection against the development of
CRC and colitis via the inhibition of tumor growth,
induction of apoptosis, reduction of oxidative damage,
and restriction of activity of co-carcinogenic enzymes.
Conversely, with diminishing such beneficial bacteria
population in gut, it advances the development of CRC.
Some bacterial species, which are linked with cancer,
are
Fusobacterium
nucleatum,
enterotoxigenic
Bacteroides
fragilis,
and
colibactin-producing
Escherichia coli. It has been found that the vast
increase of Fusobacterium nucleatum in patients with
early-stage CRC shows poor prognosis. In addition,
latest studies identified a new B type, which is known
as Enterotoxigenic Bacteroides Fragilis or ETBF. Fragilis
strain that produces Bacteroides fragilis toxin (BFT),
which activates specific cancer-promoting pathways in
colon epithelial cells, resulting in colon inflammation
linked to colorectal cancer. [59] Dysbiosis of the colon
microbiome resulted in increased interleukin-17 driven
inflammation, which promotes to the carcinogenesis
of colorectal cancer in humans. Chronic inflammation
is associated to carcinogenesis, where 20% of
individuals classified with ulcerative colitis, leading to
CRC development within 30 years of commencement.
Association Between Breast and Colorectal Cancers
Some of the studies implied the potential for an
association between breast cancer and colon cancer in
females, with the likely relationship drawn between
the extent of sex hormones and the occurrence of
colorectal cancer. Prospective exposure of breast
cancer
patients
to
the
higher
levels
of
endogenous/exogenous sex hormones owing to parity,
hormone/estrogen replacement therapy, and breast
cancer treatments (tamoxifen) may enhance the
prospective chance of getting colon cancer, which is
yet contentious. Additionally, the study indicated that
individuals with breast cancer were 60% more likely to
have colon cancer. Another research conducted by
Abu-Sbeih et al showed that patients with a previous
history of BC may be at a higher incidence rate for the
appearance of adenomatous polyps irrespective of the
age of the patient and had a 5% chance of getting
invasive CRC. Besides, it was emphasized that a
decision about colonoscopy recommendation was
based on the patient's age at the moment of BC
diagnosis. Thus, for instance, appropriate colonoscopy
screening is recommended one year after breast
cancer detection in a patient who has more than 40
years old. [60]
Moreover, the relationship between these two cancers
is further shown by the involvement of a common set
of miRNAs and their expression during disease
progression. As mentioned earlier, miR-21 is
overexpressed in breast cancer patients boosting cell
proliferation, migration, and invasion and hence works
as oncomiR, whereas miR-31, miR-143, and miR-145 are
known to be under-expressed in breast cancer patients
reducing cell proliferation. [43-47] Though, the case
with miR-21 and miR-31 in colorectal tumours shows a
distinct behavior where the overexpression of those
miRNAs may be found in colorectal patients supporting
inflammation-associated carcinogenesis. In such cases,
it is worthwhile to count the synergistic effects of
miRNAs in such cancer types that might come up as
second de novo malignancy in cancer survivors. Figure 2
shows the probable correlation with the prevalence of
colorectal cancer in females having a history of breast
cancer.
Involvement of Host miRNAs and the Microbiota in
Immune Regulation of Cancer
miRNA participates in various processes of human
physiology, such as differentiation, cell proliferation,
development,
and
apoptosis.
However,
the
development of tumours and treatment failure may be
caused by the dysregulation of miRNA expression,
biogenesis, and epigenetic regulation of miRNA genes.
[61] Such cancer-derived miRNAs can modulate immune
responses by creating an immunosuppressive tumor
microenvironment
while
suppressing
cancer
immunogenicity, thus maintaining cancer cells from
immune clearance. Immunomodulatory miRNAs (im-
miRNAs) can influence cancer immune surveillance,
which leads to immune escape of tumors. Such im-
miRNAs are involved in modulating the immune
response by modifying cancer antigen processing and
presentation. For instance, miR-27 decreases the
exposure of MHC class I to the cell surface in colorectal
cancer. In addition, miRNAs can even control PD-1
expression and influence NK cells, thereby helping
malignancies
evade
immune
surveillance.[57]
Furthermore, commensal gut microbiome components
are also required for the maturation of innate and
adaptive
host
immunity,
preserving
intestinal
homeostasis, thereby providing detection and tolerance
against opportunistic pathogen attacks and prevention
of infection. However, alteration in the microbial
community shifted immune checkpoint blockers to
result in immunological dysregulation, thereby
triggering inflammation-inducing bacteria, which
enhances chronic inflammation leading to tumor
development.[43] Several studies showed that gut
microbiome may be involved with the functioning of the
immune response by altering the expression of miRNA.
Alterations in the microbiota, miRNA transcriptome,
among other factors such as chronic stress and some
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therapy like chemotherapy trigger immunological
imbalance
in
cancer
patients
that
causes
immunodeficiency/ immunosuppression.[49] This
level of immunosuppression places them at
vulnerability to infections produced by opportunistic
pathogens like viruses, which for decades has remained
a big concern to cancer patients and oncologists.
Figure 2
Incidence of colorectal cancer among breast
cancer
patients/survivors.
Coherent
cross-talk
between the gut microbiome and host miRNAs is
preserved in the host, but dysbiosis of the gut
microbiota and inappropriate expression of many host
miRNAs can trigger malignancies like breast and colon
cancers. Alternatively, women afflicted with or who
survived from breast cancer are known to suggest a
susceptible risk of developing colon cancer. Levels of
endogenous and/or exogenous sex hormones and
differential activity of a certain common set of miRNAs
induce colorectal cancer in females with breast cancer
history.
Being a new coronavirus, the COVID-19, or coronavirus
disease of 2019, is a sort of severe acute respiratory
syndrome brought on by the SARS-CoV-2 virus, or
severe acute respiratory syndrome-coronavirus-2,
causing highly worse respiratory distress in
immunocompromised
persons
than
in
immunocompetent persons. Such a development falls
among the highlighted pathogenic attacks for
everyone, especially for cancer patients. Virus
virulence is more important in disease outcome;
besides that, many other host- associated features
including age, gender, obesity, smoking, and
comorbidities including cardiovascular disease,
diabetes mellitus, and cancer influence a lot regarding
the serious consequence of the disease.[51] Cancer
patients are recognized to be immunosuppressed
individuals, and the condition is worsened by some
kinds of treatment, making them susceptible to
infections such as COVID-19, which could be
opportunistic, resulting to serious effects in such
patients. Studies in China showed a death risk of 6% of
cancer patients who had COVID-19 infection than 1% of
non-cancer patients. Susceptibility of cancer patients
was deemed three times higher for COVID- 19 infections
with a poor prognosis due to their immune-suppression
caused by the disease and treatments administered
compared to individuals without cancer.
Different cancer types are either more or less
susceptible to viral infections, such as COVID-19.
Colorectal cancer, for example, is more susceptible to
COVID-19. Transmembrane serine protease 2 facilitates
the activation of the coronavirus spike protein, thus
increasing the entry of the virus into the target cell, and
the angiotensin-converting enzyme 2 receptor assists
the spike protein in its binding to the target cell. The
increased expression of the two proteins in lung
epithelium increases the risk of getting SARS-CoV-2.
Outside the respiratory tract, ACE2 and TMPRSS2 are
expressed in the human gastrointestinal system and
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The American Journal of Medical Sciences and Pharmaceutical Research
overexpressed in colorectal cancer. As such, the
intestinal epithelium may serve as a target for COVID-
19 virus infection that may be associated with
increased incidence of infections in colorectal cancer
patients. [51-54]
However, some miRNAs can bind to viral RNA and
prevent its translation, thus having a deleterious effect
on the viral genome. One study reported six separate
miRNAs, which were identified as the potential
regulators of human coronaviruses: miR-21-3p, miR-
195-5p, miR-16-5p, miR-3065-5p, miR-424-5p, and
miR-421.114 Alternatively, some miRNA such as miR-
27b can modulate ACE2 receptor, through which
coronavirus enter into the cells.115 Another study has
demonstrated that miRNAs 200b-3p, 200 c-3p, and 429
can regulate ACE2, while TMPRSS2 is regulated by let-
7c-5p, miRNA 98-5p, let-7 f-5p, let-7a-5p, let-7 g-5p,
let-7b-5p, miR-4458, let-7e-5p, let-7i-5p, let-7d-5p,
and miRNA 4500.116 These miRNAs can be useful
therapeutic options in modulating the proteins
involved in COVID-19 entrance, particularly in the gut,
since ACE2 and TMPRSS2 are expressed at high levels
in colorectal cancer. However, expression against the
SARS-CoV-2 genome is reduced inversely with age;
hence, the elderly population is unlikely to be reduced
by COVID-19 via miRNA-based approaches compared
to younger populations. [54]
In breast cancer, the re-activation of the DCC due to
inflammatory responses within the microenvironment
poses a danger as they had attained a dormant
condition following successful treatment of the
primary disease. DCC may be reactivated by breaking
through the dormancy of metastasis, and in situations
like the SARS-CoV-2 infection, damage caused in the
respiratory tract invokes a series of immunological
events which, in turn, provoke pro-inflammatory
responses. Such responses regulate inflammatory
responses and may induce the re-activation of DCCs,
facilitating the growth of cancer cells. [61]
Promising Therapeutic Targets of Cancer
miRNAs are modifiers of the cell involved in several
biological processes that include proliferation, cell
signaling, differentiation, stress responses, and DNA
repair. Moreover, miRNA plays a critical role in the
development, activation, and effector functions of
immune cells in innate as well as adaptive immunity.
The innate immune system would provide the primary
response to an infection, but adaptive immunity would
allow such a response to expand. miRNAs can target
major players in the innate immune systems, including
natural killer cells, macrophages, and inflammatory
cytokines and chemokines.[62] For instance, the
oncomiRs, or oncogenic miRNAs, miR-21 and miR-155,
have been shown to play a significant role in the
mechanism of immune modulation involving breast
cancer. It was shown that miR-21 displays a bi-
directional role during carcinogenesis where it also
facilitates an antitumor immune response and higher
levels of miR-115 in immune cells suggest an anti-tumor
immune response as well. Such miRNAs can be
identified as a possible immunotherapeutic target for
malignancies, such as creating inhibitory-miRNA
therapeutics based on antisense antimiRs.
Alternatively, gut microbiota has a high contribution
towards the immunotherapy of cancer where these
bacteria can influence immune activities through
alteration of the immunological check point inhibitors.
Most cancer immunotherapies work by restoring the
functions of the immune cells by inhibiting
immunological checkpoints and reconstituting the
antitumor immunity of the immune cells.[63] Immune
checkpoint blockade treatment (ICB) is one such
potential immunotherapeutic approach for a few types
of tumors where the gut microbiota has a pivotal role in
the delivery of such drugs. The anatomic location of gut
microbiota varies the efficacy of PD-1 and CTLA-4
blockades.
Enterococcus,
Ruminococcaceae,
Akkermansia, and Bifidobacterium species enhance the
efficacy of treatment of the blockade of PD-1. The genus
Bacteroides shows a biphasic effect where some strains
enhance the CTLA-4 blocking therapy and others
negatively affect the efficacy of therapy.
Gut dysbiosis may support chronic inflammatory
diseases like cancer, which allow unfavored able
bacteria to reside in the gut and negatively impacts
immunotherapy. Giving antibiotics or prebiotics along
with symbiosis can improve colonization of the
commensal microbiota within the gut through
eliminating pathogenic microbes that is well-suited to
creating antitumor immune activities. [63] Several new
trends emerge in the modern world concerning cancer
medicines, like using live or attenuated and/or
genetically engineered microbes to treat cancer.
Bacteria-assisted tumor-targeted treatment is one of
the possible ways of using bacteria as gene or medicine
delivery vehicles to treat tumours when bacteria alone
work as an efficient anticancer agent. Some of the
selected bacterial species, including Clostridia,
Bifidobacteria, and Salmonellae, are used in animal
models to express tumor suppressor genes, anti-
angiogenic genes, suicide genes, or tumor- related
antigens in a specific tumor. Moreover, bacteria are
used as immunotherapeutic agents and their tox
ins/enzymes in cancer therapy, which are powerful
drugs in the future.
CONCLUSION
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After considering all the important topics covered so
far, the identification of relevant signatures related to
gut microbiomes and host miRNAs highlighted their
role in the development of cancer through
dysregulation. Understanding these mechanisms of
microbiome and miRNA dysregulation in various
cancers is crucial for regulating the onset and spread of
cancer. Beyond that, the diagnosis, prognosis,
prediction, and recurrence of the disease may be
traced using biomarkers from the gut microbiota and
host miRNA profiles. It is essential, therefore, that the
correlation potential of two cancers that are usually
encountered together, such as breast and colorectal
cancers, should also be accounted for when making
prompt diagnosis at the onset and providing relevant
treatment following this consideration since that might
indicate synergy between both of these biomarkers for
these types of cancer. The dysregulation of miRNA,
along with the microbiota, even affects a cancer
patient's
immune
responses
to
cause
immunosuppression and increase the vulnerability to
infections. Thorough knowledge of what the gut
microbiome and miRNA do, particularly about its
behavior in cancer conditions, would be highly
beneficial in developing possible noninvasive
biomarkers for the early detection of illness in order to
minimize possible risks. As an alternative, knowing
how the gut microbiota and host miRNAs
communicate depending on expression can help in the
development of druggable targets for cancer
treatments such as miRNA-based therapies that
decrease oncomiR expression while restoring TS-miR
expression. Additionally, therapeutic targets can be
created to improve gut health and produce antitumor
immune activity by increasing beneficial bacteria and
lowering harmful ones. Commensal microbial
colonization in the gut can be improved by symbiotics,
prebiotics, and antibiotics.
To improve the antitumor environment inside the
tumor, genetically engineered bacteria either by
themselves or with traditional approaches are under
examination for potential future therapies. This
technique is referred to as bacterium-assisted tumor-
targeted therapy. Moreover, having insight into the
composition of the microbiota can make use of
immunotherapeutic methods, like the medicines
which blockade immune checkpoint for cancer
patients. In summary, it is important to understand
how host miRNAs and the gut microbiota interact and
behave, especially in relation to cancer diagnosis,
treatment, and prognosis, while obtaining the
necessary information to implement effective and
efficient therapeutic approaches.
Abbreviations
BC, breast cancer; ER+, estrogen-receptor-positive; ER-
,estrogen-receptor-negative;
PR+,
progesterone-
receptor-positive; PR-, progesterone-receptor-negative;
HER2+,human epidermal growth factor receptor 2-
positive;HER2-, human epidermal growth factor
receptor 2-nega-tive; miRNA, microRNA; CRC, colorectal
cancer; HDI, Human Development Index; CIN,
chromosomal instability; CIMP, CpG island methylator
phenotype; MSI, micro-satellite instability; oncomiR,
oncogenic
miRNAs;
TS-miRs,
tumor-suppressive
miRNAs; metastamiRs, metastasis-associated miRNA;
antagomirs, anti-miRs; AMOs, antisense anti-miR
oligonucleotides; LNA, locked nucleic acid; TNBC, triple-
negative breast cancer, TPM1, tropo-myosin; CEA,
carcinoembryonic antigen; CA15-3, cancer antigen,
TUSC2, tumor suppressor candidate 2; EGFR, epidermal
growth factor receptor, TGF-
β, transforming growth
factor beta; PDCD4, programmed cell death 4;BFT,
Bacteroides fragilis toxin; ETBF, enterotoxigenic
Bacteroides fragilis; im-miRNAs, immunomodulatory
miRNAs, PD-1, programmed cell death protein 1; NK,
natural killer; ACE2, angiotensin-converting enzyme2;
TMPRSS2, transmembrane serine protease 2, DCC,
dormant cancer cells; ICB, immune checkpoint
blockade;CTLA-4, cytotoxic T-lymphocyte-associated
protein 4.
Disclosure
: The authors report no conflicts of interest in
this work.
FUNDING
: This study received no financial support from
any organization. All expenses were covered by the
authors themselves.
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