**4. miRNA and colorectal cancer**

Colorectal cancer (CRC) is the second most common cancer among the women and third most common cancer among men. In 2016, more than 1.4 million men and women in the USA have been diagnosed with CRC [47]. Despite the availability of successful treatment options such as surgery, chemotherapy, and radiotherapy, the prognosis of CRC is not promising. Relapse or metastatic spread occurs after surgery in many CRC patients. Colorectal cancer is divided into two phenotypes according to mutational status. In chromosomal instability phenotype (CIN), high rate of inactivating mutations in adenomatous polyposis coli (*APC*) and tumor protein P53 (*TP53*) genes are found as well as activating mutations in Kirsten rat sarcoma viral oncogene homolog (*KRAS*) gene. However mutations in DNA repair genes, transforming growth factor-beta receptor II *(TGFBRII) gene, Bcl2- associated C protein (BAX) and BRAF* genes are commonly existed in microsatellite instabilityhigh tumors (MSI-H) [48]. Certainly, genomic background affects the miRNA expression in CRC, such as *TP53* mutations affect miR-145 expression levels, which is downregulated among many CRC patients [49, 50]. Furthermore, miR-193a-3p expression was found as specifically downregulated in *BRAF*-mutated CRC cases [51]. The distinction between these phenotypes became more prominent in disease progression and therapy response, which will be discussed in the following sections. In CRC, to date, totally, 1870 original studies were retrieved in PubMed (as of May 2018), in which 38 of them were clinical trials investigating miRNA expression patterns in both CRC tissue specimen and plasma samples and compared them with normal samples. Bunch of miRNAs were found to be dysregulated in CRC samples in these studies [52–54]. While some of these miRNAs are related with early stages of tumorigenesis and can be used as diagnostic markers, the others are associated with therapeutic response, resistance to chemotherapy, and survival prognosis, hence aiding the physician in making therapeutic decisions as prognostic and predictive biomarkers [55].

**35**

for tumor diagnosis.

**4.2 miRNAs in colorectal cancer prognosis**

*MicroRNAs (miRNAs) in Colorectal Cancer DOI: http://dx.doi.org/10.5772/intechopen.80828*

**4.1 miRNAs in colorectal cancer diagnosis**

blood or stool samples as well as tumor tissues [57] (**Table 1**).

Early diagnosis is essential for CRC patients since they have more favorable prognosis. Fecal blood test and colonoscopy techniques are being currently used for early screening. However, fecal blood tests are not very efficient for detecting early carcinoma formation. Colonoscopy is a gold standard technique, it reduces cancer risk about 30–75%, yet it is invasive and expensive technique and highly uncomfortable for a patient [56]. Therefore, noninvasive and inexpensive screening and diagnostic methods or biomarkers are needed. miRNAs are promising candidates for noninvasive biomarker diagnosis. Diagnostic miRNAs can be isolated from

There are different miRNA profiling studies comparing CRC samples with normal healthy tissue samples; however, each study emphasized on different set of miRNAs in CRC diagnosis and progression. According to miRNA profile study, miR-18a, -20a, -21, -29a, -92a, -106b, -133a, -143, and -145 expression levels were found to be significantly changed in CRC patients when compared with normal patients, and these markers can be used for CRC diagnosis [59]. In a systematic review, miR-106a, -30a-3p, -139, -145, -125a, and -133a were proposed as diagnostic biomarkers [60]. In another study, miR-143, -145, -21, -320, -126, -484-5p, -143, -145, -16, -125b, -21, and -106 were found to be candidate for diagnostic biomarkers [57]. While studies share some common miRNAs (such as miR143, miR145, miR106, miR21), they are differing in their list of miRNAs. In fact, the type of miRNAs can be differed due to the type of sample (blood or stool), experimental procedures, and used microRNA platforms. Another handicap of these studies is that they have been conducted with a small number of samples. Larger sample studies and additional meta-analyses are need for better determination of CRC-related diagnostic markers. Still, it can be said that miRNAs are very promising noninvasive markers

Taking part in CRC diagnosis, miRNAs are also affecting prognosis and therapeutic response. As mentioned before, the expression and deregulation of miRNAs in CRC patients are affected by chromosomal abnormalities and microsatellite instability [61, 62]. In CRC, miRNA expression dysregulation is shown especially in microsatellite instability (MSI-high) tumors. MSI-high groups are distinct population among CRC patients, which accounts for 15% of all cases, observed in hereditary cases such as Lynch syndrome or in sporadic cases mostly as a result of hypermethylation or inactivation of mismatch repair (MMR) genes [63]. These MSI tumors characterized by distinct behavior are associated with proximal tumor localization and high infiltration of lymphocytes. These phenotypes showed less distant organ metastasis than MSI stable tumors and have better prognosis [64]. Several miRNAs have been shown in participating in inactivation of several DNA mismatch repair genes, such as miR-155 downregulates mutL protein homolog 1 (MLH1), mutS homolog 2 (MSH2), and mutS homolog 6 (MSH6) mRNAs expression, whereas miR-21 targets MSH2 and MSH6 mRNA and inactivates them [65, 66]. Overall 94 miRNAs are differently expressed in microsatellite stable and in microsatellite instable tumors [67]. Upregulation (miR-17, miR-20, miR-25, miR-31, miR92, miR-93, miR-133b, miR-135a, miR-183, miR-203, and miR-223) and downregulation (miR-16, miR-26b, miR-143, miR-145, miR-191, miR-192, miR-215, and let-7a) are generally observed in MSI-high tumors [68]. miRNA expression is also differed among *TP53* and *KRAS* mutated tumors as well. miR-125p targets 3′ UTR region of p53 and represses p53 expression and accelerates the tumor growth;

*Oncogenes and Carcinogenesis*

regressed completely in few days [41].

and therapy response as an outcome [46].

**4. miRNA and colorectal cancer**

solid advanced tumors. While MRX34 treatment showed evidence of antitumor activity in a subset of patients, it exerts some toxicities in patients. Hence, there is need for further studies for improving tolerability among the patients [35, 36]. In addition to tumor suppressor miRNAs, miRNAs behave like oncogenes, called as "oncomiRs." mir-21 is the first miRNA identified as oncogenic; it is significantly upregulated in many tumors including colon cancer, breast cancer, hepatocellular carcinoma, and glioblastoma [37]. miR-21 overexpression contributes to cell proliferation and antiapoptotic responses by targeting important downstream proteins such as phosphotensin homolog (PTEN), programmed cell death protein 4 (PDC4), and tropomyosin I [38–40]. Besides this, miR-21 was shown to be bona fide oncogene by causing pre-B-cell lymphoma in mouse models by overexpression. When mir-21 expression was inactivated, tumors

As the importance of miRNAs became evident, miRNA expression profiles for each tumor type have been studied with several methodologies including microarray, QRT-PCR, and next-generation sequencing [15, 42]. miRNA expression profiles can reflect embryonic or development origin of the tissue and able to classify the origin of tissue with high accuracy (>90%), even separate cell subtypes (stem cells vs. progenitor cells) in the same tissue [43–45]. These miRNA profiling studies open the way for biomarker studies. In the biomarker studies, it is aimed to find diagnostic, prognostic, and predictive markers for better characterization of the disease

Colorectal cancer (CRC) is the second most common cancer among the women and third most common cancer among men. In 2016, more than 1.4 million men and women in the USA have been diagnosed with CRC [47]. Despite the availability of successful treatment options such as surgery, chemotherapy, and radiotherapy, the prognosis of CRC is not promising. Relapse or metastatic spread occurs after surgery in many CRC patients. Colorectal cancer is divided into two phenotypes according to mutational status. In chromosomal instability phenotype (CIN), high rate of inactivating mutations in adenomatous polyposis coli (*APC*) and tumor protein P53 (*TP53*) genes are found as well as activating mutations in Kirsten rat sarcoma viral oncogene homolog (*KRAS*) gene. However mutations in DNA repair genes, transforming growth factor-beta receptor II *(TGFBRII) gene, Bcl2- associated C protein (BAX) and BRAF* genes are commonly existed in microsatellite instabilityhigh tumors (MSI-H) [48]. Certainly, genomic background affects the miRNA expression in CRC, such as *TP53* mutations affect miR-145 expression levels, which is downregulated among many CRC patients [49, 50]. Furthermore, miR-193a-3p expression was found as specifically downregulated in *BRAF*-mutated CRC cases [51]. The distinction between these phenotypes became more prominent in disease progression and therapy response, which will be discussed in the following sections. In CRC, to date, totally, 1870 original studies were retrieved in PubMed (as of May 2018), in which 38 of them were clinical trials investigating miRNA expression patterns in both CRC tissue specimen and plasma samples and compared them with normal samples. Bunch of miRNAs were found to be dysregulated in CRC samples in these studies [52–54]. While some of these miRNAs are related with early stages of tumorigenesis and can be used as diagnostic markers, the others are associated with therapeutic response, resistance to chemotherapy, and survival prognosis, hence aiding the physician in making therapeutic decisions as prognostic and

**34**

predictive biomarkers [55].
