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Year : 2012  |  Volume : 1  |  Issue : 4  |  Page : 211-216

MicroRNAs in colorectal cancer: A new and promising early diagnostic option

1 Department of Biochemistry, JSS Medical College, JSS University, Mysore, Karnataka, India
2 Department of Surgery, JSS Medical College, JSS University, Mysore, Karnataka, India

Date of Web Publication27-Feb-2013

Correspondence Address:
Akila Prashant
Department of Biochemistry, JSS University, Mysore, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2278-344X.107819

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In spite of advances in diagnostic techniques, surgery, chemotherapy and radiotherapy, colorectal cancers remain undefeated. In the absence of screening, colorectal cancers are diagnosed in an advanced stage when regional and distant metastasis is present. Hence, the hope for control is primary prevention or early diagnosis. Western lifestyle and diet have been implicated in the causation of colon cancers. However, it is still a controversy whether this is due to excess calories, high fat content, genotoxic agents, or lack of protective agents present in vegetables and fruits. Therefore, recommending a specific cancer prevention diet can have fallacies. In this context reduction in cancer mortality can be achieved by screening population at high risk. The colorectal cancers require investigative modalities like colonoscopy, sigmoidoscopy or fecal occult blood testing (FOBT) for screening. Colonoscopy is the most sensitive and specific of all the available colorectal screening tests, whereas the sensitivity and specificity for FOBT and sigmoidoscopy are much lower. Although performance of FOBT is relatively inexpensive, sigmoidoscopy and colonoscopy must be performed by trained endoscopists and are more expensive. Moreover, lack of awareness that colorectal cancer is a prevalent and serious disease, concerns about the potential discomforts of colorectal cancer procedures or of the preparations for screening appear to be potential barriers for colorectal cancer screening. MicroRNAs (miRNAs) have roles in colon carcinogenesis; therefore, may be useful biomarkers for colorectal carcinoma (CRC). They are short ribonucleic acid (RNA) molecules having very few nucleotides compared with other RNAs. miRNAs have been studied intensively in the field of oncological research, and emerging evidence suggests that altered miRNA regulation is involved in the pathogenesis of cancers. This review summarizes the use of miRNA in the early diagnosis of colorectal cancers.

Keywords: MicroRNA, colorectal cancer, diagnostic biomarker

How to cite this article:
Prashant A, Vishwanath P, Nataraj SM, Gurusiddappa S, Devegowda D. MicroRNAs in colorectal cancer: A new and promising early diagnostic option. Int J Health Allied Sci 2012;1:211-6

How to cite this URL:
Prashant A, Vishwanath P, Nataraj SM, Gurusiddappa S, Devegowda D. MicroRNAs in colorectal cancer: A new and promising early diagnostic option. Int J Health Allied Sci [serial online] 2012 [cited 2021 Sep 28];1:211-6. Available from: https://www.ijhas.in/text.asp?2012/1/4/211/107819

  Introduction Top

Colorectal cancer (CRC) has traditionally been one of the commonest malignant disorders in western populations, whereas cancers of the upper gastrointestinal tract (esophagus and stomach) and liver have predominated in the east. However, during the past few decades, there have been remarkable changes in the incidence of CRC in Asian countries. Some of the more developed and westernized Asian countries have already experienced a rapidly rising trend in CRC. In all the Indian cancer registries, the digestive system as a whole is the commonest cancer site group in men. However in women, cancer involving the breast is most frequent followed by the genital organs and the digestive systems. [1] Diet is regarded as the most important risk factor for colon cancer. Consumption of vegetables and fibers is preventive while consumption of total and saturated fats, animal and total proteins may increase the risk. [2] The trend in the incidence of colon, rectum and liver cancer has been shown to increase in all the cancer registries in India. Statistical significant increase is noticed in Chennai, Bangalore and Delhi registries for cancer of colon. [3]

Changes in the expression profiles of miRNAs have been observed in a variety of human tumors, including CRC. [4] Various studies have indicated that miRNAs play a role as tumor suppressors and oncogenes and hence have a great potential as a novel and minimally invasive biomarker for the diagnosis of CRC, which has been compared favorably with fecal occult blood test.

  Global Burden of Colorectal Carcinoma Top

CRC is the second leading cause of cancer death in the United States. In women, it ranks third after lung and breast cancer, and in men, it ranks third after lung and prostate cancer. In 2001, an estimated 135,400 cases were diagnosed and an estimated 56,700 deaths occurred in the United States. [5] However, recent studies have shown that CRC incidence rates have declined in the US. This decline may have been due, in part, to increased screening and polyp removal. In China, CRC remains the fifth most common cancer type and the fourth most common cause of cancer-related death. [6] GLOBOCON 2008 report has shown that CRC is the third most common cancer in men (663,000 cases, 10% of the total) and the second most common in women (571,000 cases, 9.4% of the total) worldwide. Almost 60% of the cases occur in developed regions. Incidence rates vary 10-fold in both sexes worldwide, the highest rates being estimated in Australia/New Zealand and Western Europe, the lowest in Africa (except Southern Africa) and South-Central Asia, and are intermediate in Latin America. Incidence rates are substantially higher in men than in women (overall sex ratio of the ASRs 1.4:1). [7]

About 608,000 deaths from CRC are estimated worldwide, accounting for 8% of all cancer deaths, making it the fourth most common cause of death from cancer. As observed for incidence, mortality rates are lower in women than in men, except in the Caribbean. There is less variability in mortality rates worldwide (6-fold in men, 5-fold in women), with the highest mortality rates in both sexes estimated in Central and Eastern Europe (20.1 per 100,000 for male, 12.2 per 100,000 for female) and the lowest in Middle Africa (3.5 and 2.7, respectively). [7] Data from the Cancer Base of the International Agency for Research on Cancer (IARC) show that the incidence in many affluent Asian countries is similar to that in the west. The age-standardized rate of CRC per 100,000 men is 49.3 in Japan, 24.7 in South Korea, and 35.1 in Singapore, compared with 44.4 in North America and 42.9 in Western Europe.

The increase in CRC in economically transitioning countries may reflect the adoption of western lifestyles and behaviors. Many of the established and suspected modifiable risk factors for CRC, including obesity, physical inactivity, smoking, heavy alcohol consumption, a diet high in red or processed meats, and inadequate consumption of fruits and vegetables are also factors associated with economic development or westernization. The male CRC incidence rates in the Czech Republic, Slovakia and Japan have not only exceeded the peak incidence observed in the United States and other long-standing developed nations, but also continue to increase.

  Burden of Colorectal Carcinoma in India Top

India, a country in transition from a developing to a developed nation, is home to more than one billion people. Cancer rates in India are rising as development progresses, with a changing profile of burden at different cancer sites. In India the first population-based cancer registry was established in Mumbai (Bombay) by the Indian Cancer Society in 1964 covering the urban population of Greater Mumbai. National Cancer Registry Program (NCRP) was launched by the Indian Council of Medical Research (ICMR) in 1981, establishing another two population-based cancer registries at Chennai and Bangalore. Subsequently, another two new population-based cancer registries were commissioned by ICMR under the network of NCRP at Bhopal and New Delhi in 1986. [3] The incidence rates of various digestive cancers in India are either moderate or low compared to other parts of the world. The esophagus is the leading site of cancer for men and women in India. This is followed by the stomach in both men and women. In men, rectum is the third commonest cause, with 10,462 new cases followed by liver, colon, pancreas and gallbladder. In women, gallbladder is the third most common cancer, with 7,360 cases followed by rectum, colon, liver and pancreas. [8] However, the incidence of esophageal and stomach cancer is declining spontaneously in India; at the same time, the incidence of gallbladder, colon, liver and pancreas cancer is rising. Among these the incidence and mortality rates for cancer of the colon are rising, particularly in areas where the risk was formally low. These changes have been accompanied by changing ratios between the sub sites within the colon, with left-sided tumors (of the descending and sigmoid colon), becoming more frequent. The rising incidence of CRC may be due to increase in migration of rural population to the cities, increase in life expectancy and changes in lifestyle.

miRNA discovery

Cancer is fundamentally a genetic and epigenetic disease requiring the accumulation of genomic alterations that inactivate tumor suppressors and activate proto-oncogenes. Classical tumor suppressors such as retinoblastoma 1 and p53 and oncogenes such as MYC and RAS have been extensively studied and found to be involved in complicated interacting pathways that regulate cell cycle progression and apoptosis. [9],[10] Cells have developed several safeguards to ensure that cell division, differentiation and death occur correctly and in a coordinated fashion, both during development and in the adult body. Many regulatory factors switch on or off genes that direct cellular proliferation and differentiation. Damage to these genes, tumor-suppressor genes and oncogenes, results in the formation of cancers. Most tumor-suppressor genes and oncogenes are first transcribed from DNA into RNA, and are then translated into protein to exert their effects. While recent studies of the cancer genome have focused mainly on protein-coding genes, little is known about alterations of functional non-coding sequences in cancer. [11],[12] However, these small non-coding molecules initially referred to as "junk" RNA have shown to function as tumor suppressors and oncogenes. These molecules, now referred to as microRNA (miRNA) had perhaps escaped detection because of their size, as avid gene hunters were mainly interested in long mRNAs disregarding the shorter RNAs. [13] Understanding of miRNAs has grown significantly; in 2006 Andrew Z. Fire and Craig C. Mello won the Nobel Prize for their work on RNA interference and regulation of gene expression by miRNAs. miRNAs comprise an abundant class of endogenous, small non-coding RNAs 18-25 nucleotides in length that repress protein translation through binding to target mRNAs. They are highly conserved in sequence between distantly related organisms, indicating their participation in essential biological processes. It is well known today that miRNAs have very important regulatory functions in basic biological processes such as development, cellular differentiation, proliferation and apoptosis that affect major biological systems like stemness, immunity and cancer. [12],[14] miRNAs were first identified in 1993. Since its discovery, miRNAs have been identified in diverse animals and plants that utilize these RNAs to regulate gene expression. In humans, over 400 miRNAs have been identified and it is predicted that the human genome encodes up to 1000 miRNAs. [15],[16]

miRNA biogenesis

miRNAs are transcribed by an RNA polymerase II into a capped and poly-adenylated precursor, called pri-miRNA. A dsRNA-specific ribonuclease called Drosha, in conjunction with its binding partner DGCR8 (DiGeorge syndrome critical region gene 8, or Pasha), cleaves the pri-miRNA into a hairpin-shaped RNA precursor (pre-miRNA), approximately 70-100 nucleotides (nt) long. Translocated into the cytoplasm by means of exportin 5, the pre-miRNA is cleaved into an 18-24 nt duplex by a ribonucleoprotein complex, composed of a ribonuclease III (Dicer) and HIV-1 transactivating response RNA-binding protein (TRBP). Finally, the duplex interacts with a large protein complex called RNA-induced silencing complex (RISC), which includes proteins of the Argonaute family (Agol-4 in humans), which drives one strand of the duplex to the 3Ͳ untranslated region of the target mRNAs. Overall, the effect of miRNAs is to modulate the expression of the target mRNAs either by mRNA cleavage or by translational repression. [17] However, researchers have discovered that miRNAs can also increase the expression of a target mRNA. [18] Each miRNA can target several different transcripts. [19] In addition, the same mRNA can be targeted by several miRNAs. [20]

miRNAs as tumor suppressors and oncogenes

miRNA expression patterns are highly specific for cell type and cellular differentiation status. It is therefore likely that much of the aberrant miRNA expression observed in tumors is a secondary consequence of the loss of normal cellular identity that accompanies malignant transformation. Thus, down-regulation of a miRNA in a given tumor type is not necessarily indicative of a causative role in tumorigenesis. The case that a miRNA functions as a tumor suppressor or oncogene is strengthened by at least four types of evidence: 1. data demonstrating widespread dysregulation in diverse cancers, 2. gain or loss of miRNA function in tumors owing to deletion, amplification or mutation, 3. direct documentation of tumor-suppressing or tumor-promoting activity using animal models and 4. the identification and verification of cancer-relevant targets that illuminate mechanisms through which the miRNA participates in oncogenesis. [21]

miRNAs as diagnostic biomarkers in solid tumors

In lung cancer, out of the 352 miRNAs analyzed in 144 matched lung cancer-normal pairs 43 miRNAs were differentially expressed, which can act as biomarkers of this disease and its histological subtypes. [22] In particular, the let-7 miRNA family has been proposed to function in tumor suppression because reduced expression of let-7 family members is common in non-small cell lung cancer (NSCLC). Let-7 functionally inhibits non-small cell tumor development. Ectopic expression of let-7g in K-Ras G12D -expressing murine lung cancer cells induced both cell cycle arrest and cell death. [23] Hence, silencing of let-7 family members is involved in human lung carcinogenesis. In breast cancer, a specific signature composed of 29 differentially expressed miRNAs, can differentiate between cancerous and normal breast tissues. [24] In particular, high levels of miR-21 and miR-155, and low expression of miR-10b, -125b and -145 are associated with malignant phenotype. In gastric cancer tissue, 22 miRNAs are up-regulated and 13 down-regulated when compared to non-tumor mucosa. [25] In prostate cancer, about 51 differentially expressed miRNAs in cancerous versus normal tissues have been identified. [26] In pancreatic cancer, 21 over-expressed and four down-regulated miRNAs allow a differential diagnosis among pancreatic adenocarcinoma, normal pancreas and chronic pancreatitis. [27] A signature of eight deregulated miRNA was identified in hepatocellular carcinoma (HCC) versus normal liver tissue, which included three up-regulated and five down-regulated miRNAs. [28]

miRNAs as prognostic biomarkers in solid tumors

In NSCLC, high levels of miR-155 and low expression of let-7a correlate with poorer overall survival. [22] Also, a prognostic signature of five miRNAs (namely let-7a, miR-221, miR-137, miR-372 and miR-182) can be used to determine the risk of relapse in NSCLC. [29] In breast cancer, low levels of miR-30 correlate with estrogen receptor- and progesterone receptor- negative tumors, whereas high levels of miR-213 and miR-203 are found in high-stage tumors. [24] High expression of miR-21 is associated with increased invasion and metastatic potential. [30] A progression-related signature in gastric cancer was identified in which miR-125b, miR-199a and miR-100 were the most important miRNAs involved. Low expression of let-7g and miR-433 and high expression of miR-214 were associated with an unfavorable outcome in overall survival. [25] The expression of miR-96 was associated with cancer recurrence after radical prostatectomy, demonstrating the high significance of this miRNA as prognostic biomarker in prostate cancer. [31] In pancreatic cancer, a group of six miRNAs is associated with better prognosis in node-positive patients, whereas high levels of miR-196a correlate with a poorer prognosis. [27] High levels of miR-125b were associated with a good overall survival in HCC patients, [32] whereas high expression of miR-221 is a negative prognostic factor. [33]

miRNAs as biomarkers in colorectal cancer

As with other human cancers, several miRNAs are up- or down-regulated in this tumor type. miR-31, miR-96, miR-135b and miR-183 have been found to be up-regulated in CRC; transcription factor CHES1 (which is involved in repressing apoptosis) is a potential target of miR-96. [34] High expression of gene encoding miR-21 correlates with reduced expression of the gene encoding tumor suppressor protein PDCD4. miR-135a and miR135b are up-regulated, and this up-regulation correlates with reduced expression of the APC (adenomatous polyposis coli) gene. [35] miR-143 and miR-145 are both down-regulated in CRC. The genes encoding these miRNAs are both located on 5q23, and these miRNAs possibly originate from the same primary miRNA. [36],[37] miR-126 promotes cell proliferation through modulation of phosphotidyl inositol 3-kinase signaling. [38] miR-133b is also down-regulated, and one of its putative targets is KRAS. [39] KRAS is a member of the Ras family of proteins, which regulates signaling pathways involved in cellular proliferation, differentiation and survival. Also, miR-192, -194 and -215 are significantly down-regulated in CRC tissues and cancer cell lines compared to non-tumor counterparts. Moreover, the expression levels of miR-192, -194 and -215 are demonstrated to be associated with increased tumor sizes. [40] In addition, specific and combined mRNA/miRNA gene expression profiles are able to identify the occurrence of microsatellite instability in CRCs at the time of diagnosis. [41]

miRNAs in serum/plasma

The potential to use miRNAs as biomarkers for disease is strengthened by their stability in human serum and plasma. [42],[43] Instead of using invasive procedures to extract tissue from patients' tumors, miRNAs can be measured directly from the patients' blood products. The miRNA expression profile from serum of healthy individuals was shown to be significantly different from that of patients with lung cancer, CRC and diabetes. [43] Another study investigating the expression of miRNAs in plasma found that miR-141 can serve as a biomarker for prostate cancer with a sensitivity of 60% and a specificity of 100%. [42] Eight miRNAs from peripheral blood as circulating biomarkers of ovarian cancer were detected, which circulated enclosed in tumor-derived exosomes of endocytic origin. [44] Also, high levels of miR-25 and miR-223 were seen in the serum of NSCLC patients when compared to normal healthy controls. [42]

Advantages of using miRNA expression profile

There are several advantages of using miRNA expression profiling instead of its mRNA counterpart for biomarker identification and also for routine diagnostics. 1. Since a single miRNA can regulate the expression of more than 100 mRNAs simultaneously, microarrays of 217 miRNAs have much higher information content than 16,000 mRNAs in distinguishing different tissues and tumors. [45] 2. It is relatively easier to discover reliable biomarkers from the hundreds of miRNA candidates discovered to date than from over 40,000 genes. 3. Due to their small size and stem-loop structure, miRNAs are relatively more stable and less subjected to degradation during fixation and sample processing. A good correlation was observed when miRNA-expression profiles from fresh frozen CRC tissues were compared with that of formalin-fixed paraffin-embedded CRC tissues. Also, differing formalin fixation times which are inevitable in a routine pathology laboratory did not significantly influence the expression of miRNAs. [46] 4. Finally, miRNAs can be visualized at the cellular and sub-cellular levels by conventional as well as fluorescence in situ hybridization. [47]

miRNA-detection technologies

There are several methods for detecting miRNAs and/or determining miRNA profiles of particular cell types, such as microarrays, bead-based arrays, quantitative real-time PCR and next generation sequencing. The principle of miRNA microarrays is based on the Watson-Crick base pairing of nucleic acids. A set of oligonucleotide capture probes are spotted on glass slides, and a sample of extracted RNA enriched for small-molecule RNAs is allowed to hybridize with the capture probes. In bead-based arrays, probes are coupled to carboxylated polystyrene microspheres that incorporate variable mixtures of 2 fluorescent dyes that allow a flow cytometer to identify each microsphere by its unique color. Quantitative real-time PCR can also be used to detect miRNAs. Quantification of mature miRNAs usually requires reverse transcription of the miRNA with a stem-loop primer. The cDNA is then used in the real-time PCR reaction. Recently, "digital gene expression" by next-generation sequencing has been introduced as a promising, new platform for assessing the copy number of transcripts, thereby providing a digital record of the numerical frequency of a sequence in a sample. However, it is still in its infancy, while microarray probes have been Tm (melting temperature) normalized and perfected over several array generations.

Future trends in miRNA

The biosynthesis, maturation and activity of miRNAs can be manipulated with various oligonucleotides that encode the sequences complementary to mature miRNAs. [48] Over-expression of miRNAs can be induced either by using synthetic miRNA mimics or chemically modified oligonucleotides. Conversely, miRNAs can be silenced by antisense oligonucleotides and antagomirs. Cross-sensitivity with endogenous miRNAs and lack of specificity for cancer cells can cause non-specific side effects during miRNA modulation therapy. However, the use of an effective delivery system and less toxic synthetic anti-miRNA oligonucleotides may minimize such side effects. [49]

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