Elsevier

Biomedicine & Pharmacotherapy

Volume 97, January 2018, Pages 1319-1330
Biomedicine & Pharmacotherapy

Review
MicroRNAs as novel biomarkers for colorectal cancer: New outlooks

https://doi.org/10.1016/j.biopha.2017.11.046Get rights and content

Abstract

Colorectal cancer is one of the most prevalent cancers with high mortality in the world. MicroRNAs are a class of small non-coding RNAs that regulate gene expression through targeting mRNAs. MicroRNAs involve in many biological and pathological processes such as cell growth, differentiation, apoptosis. etc. Dysregulation of miRNAs expression patterns have been reported in many tumors including Colorectal Cancer. Various studies indicate that miRNAs can be utilized as diagnostic and prognostic biomarkers for evaluation of tumor initiation, development, invasion, metastasis and response to chemotherapeutic drugs. Numerous investigations have also shown dysregulation of miRNAs in tissue samples and body fluids such as serum, plasma and fecal samples from CRC patients. Recently, several studies have demonstrated that miRNAs have regulatory roles in response to anti-cancer drugs and suggested them as predictive factors for successful treatment. In this review, we highlight the facts concerning tumor suppressor miRNAs and oncomiRs in CRC; by emphasizing their importance in different signaling pathways such as the Wnt/β catenin activation, EGFR pathway, (TGF-ß) and the TP53 network and then their potential as biomarker and targets for cancer treatment.

Introduction

Colorectal Cancer (CRC) is the third most prevalent malignancy after lung and breast cancer all over the world, especially in developed countries [1]. In many areas of the world, incidence rates of CRC are rapidly increasing. Prevalence and mortality rates of CRC have been estimated as high as 1,200,000 and 600,000 cases/year respectively [2]. In spite of diagnosing and treatment of this cancer, patients’ survival is vastly correlated with tumor stage at the time of diagnosis and 40–50% of patients die due to distant metastasis [3], [4]. Genetic and epigenetic alterations can dysregulate tumor suppressor genes and oncogenes in CRC [5].

MicroRNAs are a class of 21–25 nucleotide non-coding RNAs known to post-transcriptionally regulate gene expression and control different biological mechanisms such as activation of immune system and inflammatory responses, regulation of cholesterol homeostasis, osteogenesis regulation, etc. [6], [7], [8], [9]. Affecting oncogenes and/or tumor suppressor genes, Dysregulated miRNAs are implicated in the pathogenesis of CRC [10]. Since, the expression patterns of miRNAs are different in tumor tissues and body fluids such as plasma, serum, urine, saliva, etc. [6]. in comparison with normal controls; thus miRNAs are classified as oncomiR and tumor suppressor miRNA and numerous of them can be used as diagnostic, prognostic and predictive biomarkers of CRC [11], [12]. Furthermore, different studies have demonstrated that miRNAs are highly potential molecules to be utilized as therapeutic agents in CRC therapy [10]. Given these, interventions such as inhibition of oncomiRs and restoration of tumor suppressor microRNAs, might be beneficial for CRC treatment [12].

In this review, we summarize new outlooks of miRNAs on the issue of their functioning as oncomiRs or tumor suppressors in CRC through upregulation and downregulation of target genes with accentuating their targets, different molecular mechanisms, and significance of their application as a novel target in CRC diagnosis, prognosis and potential treatment.

Section snippets

Biogenesis of miRNA

Involving several enzymes and diverse cellular compartments, biogenesis of miRNAs is a complex multipart process with different phases [13]. Primarily, the process starts in the nucleus where miRNA genes are transcripted by RNA Polymerase II and primary miRNAs with variable length (1–3 kb) in the stem-loop form are resulted [14], [15]. Through next step in the nucleus, DROSHA and its cofactor DGCR8 cleave the stem-loop structures into short 70 nucleotide precursor-miRNAs (pre-miRNA), which will

General features of miRNA

MicroRNAs (miRNAs) are a family of small, evolutionarily conserved, noncoding RNA molecules (21–25 nucleotides in length) in vertebrates, plants, and protozoa [23] that play an important role in post-transcriptional gene regulation [24]. These molecules exert regulating effects on gene expression by inhibiting translation and causing degradation of target messenger RNA (mRNA) [25].

In 1993, Lee et al. were the first ones to indicate the role of lin-4 in regulation of some biological processes in

Role of miRNAs in colorectal cancer signaling pathways

According to the literature, there are many miRNAs playing different roles in CRC indisputable upregulation, downregulation or switching off of which can be important in the carcinogenesis of CRC [10], [35], [36].

MiRNAs are generally classified as tumor suppressor miRNAs and oncomiRs according to their function and status in cancers. OncomiRs are known to downregulate tumor suppressor genes, by contrast, tumor suppressor miRNAs are responsible for downregulation of oncogenes, and are mostly

Tissue miRNAs as CRC biomarkers

Abnormal expression of miRNAs has different effects on carcinogenesis of the large bowel and leads to formation of adenomas and carcinomas. There is a wide range of up-regulated and/or down-regulated miRNAs in CRC found in cell lines, tumors and healthy tissues which may associated with patient’s diagnosis, prognosis and response to therapeutic agents (Fig. 3).

MiR-143 and miR-145 has been reported to be down-regulated in different stages of colorectal tissue for the first time [39]. Decreased

Circulating miRNAs as CRC biomarkers

After discovery of miRNAs and the correlation between particular miRNAs with CRC, circulating miRNAs have been considered as diagnostic and prognostic biomarkers.

Different cells can express hundreds of copies of certain miRNA alone, and cancer cells are not separated from this. Divers efforts have been made to identify CRC-specific miRNA transcripts as prospective diagnostic biomarkers which can be used to develop precancerous stage detection [4], [114].

For using miRNA as a diagnostic

Involvement of miRNAs in drug resistance

Chemotherapy is the imperative method of therapeutic strategy for patients with CRC. Five-fluorouracil (5-Fu), oxaliplatin, doxorubicin, paclitaxel and monoclonal antibodies have been applied in CRC therapy [153].

Nevertheless, many patients resist to anticancer drugs during the treatment and it is major obstacle for efficient response to chemotherapeutic agents [154]. Several studies have focused on miRNAs regulatory roles in the induction of chemo-resistance and their involvement in the

Targeting miRNAs for treatment of CRC

As mentioned previously, dysregulation of miRNAs expression levels in cancers might influence cancer phenotype. Manipulation of miRNAs pathways might be applied as a therapeutic strategy and intervention tool for inhibition of growth, invasion, metastasis, angiogenesis, induction of apoptosis and sensitivity to therapeutic mediators [193], [194].

In recent years, evidences have shown that gene therapy may be effective for CRC and may inhibit progression of tumor cells by manipulating of the

Conclusion

After the discovery of miRNAs as post-transcriptional regulators, numerous studies have focused on the role of miRNAs in tumorigenesis and development of tumor cells including cell growth, angiogenesis, invasion, metastasis, apoptosis, and drug-resistance.

Regarding CRC, there are several mechanisms involved in its progression including over-growth, loss of apoptotic regulation, invasion, angiogenesis and maintenance of cancer stem cells (CSCs).

One of the reasons for these alterations is miRNAs

References (200)

  • N. Yamada et al.

    Tumor-suppressive microRNA-145 targets catenin δ-1 to regulate Wnt/β-catenin signaling in human colon cancer cells

    Cancer Lett.

    (2013)
  • J. Yang et al.

    Adenomatous polyposis coli (APC) differentially regulates β-catenin phosphorylation and ubiquitination in colon cancer cells

    J. Biol. Chem.

    (2006)
  • S.A. Danielsen et al.

    Portrait of the PI3K/AKT pathway in colorectal cancer

    Biochim. Biophys. Acta (BBA)—Rev.Cancer

    (2015)
  • S. Velho et al.

    The prevalence of PIK3CA mutations in gastric and colon cancer

    Eur. J. Cancer

    (2005)
  • W. Wu et al.

    MicroRNA-32 (miR-32) regulates phosphatase and tensin homologue (PTEN) expression and promotes growth, migration, and invasion in colorectal carcinoma cells

    Mol. Cancer

    (2013)
  • Z. Wei et al.

    miR-181a mediates metabolic shift in colon cancer cells via the PTEN/AKT pathway

    FEBS Lett.

    (2014)
  • J. Zhu et al.

    MiR-20b,-21, and-130b inhibit PTEN expression resulting in B7-H1 over-expression in advanced colorectal cancer

    Hum. Immunol.

    (2014)
  • J. Massagué et al.

    TGFβ signaling in growth control, cancer, and heritable disorders

    Cell

    (2000)
  • J. Massagué

    TGFβ in cancer

    Cell

    (2008)
  • W. Zhang et al.

    MicroRNA-301a promotes migration and invasion by targeting TGFBR2 in human colorectal cancer

    J. Exp. Clin. Cancer Res.

    (2014)
  • X. Xu et al.

    MicroRNA-490-3p inhibits colorectal cancer metastasis by targeting TGFβR1

    BMC Cancer

    (2015)
  • Q. Li et al.

    MicroRNA-25 functions as a potential tumor suppressor in colon cancer by targeting Smad7

    Cancer Lett.

    (2013)
  • F. Zhang et al.

    MicroRNA-187, a downstream effector of TGFβ pathway, suppresses Smad-mediated epithelial–mesenchymal transition in colorectal cancer

    Cancer Lett.

    (2016)
  • H. Hermeking

    p53 enters the microRNA world

    Cancer Cell

    (2007)
  • T.-C. Chang et al.

    Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis

    Mol. Cell

    (2007)
  • N. Raver-Shapira et al.

    Transcriptional activation of miR-34a contributes to p53-mediated apoptosis

    Mol. Cell

    (2007)
  • D.M. Parkin et al.

    Global cancer statistics, 2002

    CA Cancer J. Clin.

    (2005)
  • A. Jemal et al.

    Global cancer statistics

    CA Cancer J. Clin.

    (2011)
  • M. Gonzalez-Pons et al.

    Colorectal cancer biomarkers: where are we now?

    BioMed Res. Int.

    (2015)
  • T. Armaghany et al.

    Genetic alterations in colorectal cancer

    Gastrointest. Cancer Res.: GCR

    (2012)
  • D. Madhavan et al.

    Cancer diagnosis and prognosis decoded by blood-based circulating microRNA signatures

    Front. Genet.

    (2013)
  • A.D. Thome et al.

    microRNA-155 regulates alpha-synuclein-induced inflammatory responses in models of Parkinson disease

    J. Neurosci.

    (2016)
  • K.J. Rayner et al.

    MiR-33 contributes to the regulation of cholesterol homeostasis

    Science

    (2010)
  • W. Ding et al.

    miR-30e targets IGF2-regulatedosteogenesis in bone marrow-derived mesenchymal stem cells, aortic smooth muscle cells, and ApoE−/− mice

    Cardiovasc. Res.

    (2015)
  • O. Slaby et al.

    MicroRNAs in colorectal cancer: translation of molecular biology into clinical application

    Mol. Cancer

    (2009)
  • X. Wu et al.

    The potential value of miR-1 and miR-374b as biomarkers for colorectal cancer

    Int. J. Clin. Exp. Pathol.

    (2014)
  • S.I. Rothschild

    microRNA therapies in cancer

    Mol. Clin. Ther.

    (2014)
  • L. Bonfrate et al.

    MicroRNA in colorectal cancer: new perspectives for diagnosis, prognosis and treatment

    J. Gastrointest. Liver Dis.

    (2013)
  • M. Ha et al.

    Regulation of microRNA biogenesis

    Nat. Rev. Mol. Cell Biol.

    (2014)
  • M. Li et al.

    MicroRNAs: control and loss of control in human physiology and disease

    World J. Surg.

    (2009)
  • B. Wijnhoven et al.

    MicroRNAs and cancer

    Br. J. Surg.

    (2007)
  • Y. Feng et al.

    A comprehensive analysis of precursor microRNA cleavage by human dicer

    RNA

    (2012)
  • Y.-K. Kim et al.

    Re-evaluation of the roles of DROSHA, exportin 5, and DICER in microRNA biogenesis

    Proc. Natl. Acad. Sci.

    (2016)
  • B. Mansoori et al.

    Micro-RNAs: the new potential biomarkers in cancer diagnosis, prognosis and cancer therapy

    Cell. Mol. Biol. (Noisy-le-Grand, France)

    (2015)
  • A. Esquela-Kerscher et al.

    Oncomirs—microRNAs with a role in cancer

    Nat. Rev. Cancer

    (2006)
  • P. Barbara et al.

    Polymorphisms in microRNA genes as predictors of clinical outcomes in colorectal cancer patients

    Carcinogenesis

    (2014)
  • B.J. Reinhart et al.

    The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans

    Nature

    (2000)
  • X. Luo et al.

    MicroRNA signatures: novel biomarker for colorectal cancer?

    Cancer Epidemiol. Biomark. Prev.

    (2011)
  • M. van Kouwenhove et al.

    MicroRNA regulation by RNA-binding proteins and its implications for cancer

    Nat. Rev. Cancer

    (2011)
  • Y. Dong et al.

    MicroRNA dysregulation as a prognostic biomarker in colorectal cancer

    Cancer Manage. Res.

    (2014)
  • Cited by (0)

    View full text