**4.2 miRNAs in colorectal cancer prognosis**

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;


*Abbreviations: Bcl-2, B cell lymphoma-2; E2F, E2F transcription factor 1; CDKN1A, cyclin-dependent kinase inhibitor 1A; KRAS, Kirsten rat sarcoma viral oncogene homolog; PTEN, phosphotensin homolog; BECN1, Beclin 1; ATG16L1, autophagy-related 16 like 1; SQSTM1, sequestosome 1; PDCD4, programmed cell death 4; SPRY2, sprouty RTK signaling antagonist 2; DNMT3, DNA methyl transferase 3; FRAT1, WNT signaling pathway regulator; PHLPP2, PH domain leucine-rich repeat protein phosphatase 2; VHL, von Hippel-Lindau tumor suppressor; Cdk6, cyclin-dependent kinase 6; Cdc25, cell division cycle 25A; HMGA2, high-mobility group gene; P21, CDKN1A, cyclindependent kinase inhibitor 1A; E2F1, E2F transcription factor 1; MCL1, BCL2 family apoptosis regulator; BCL2L2, BCL2 like 2; EGFR, epidermal growth factor receptor; IRS-1, insulin receptor substrate 1; ATM, ataxia telangiectasia mutated; ABL1, v-abl Abelson murine leukemia viral oncogene homolog 1; TP63, tumor protein p63; STMN1, stathmin 1; GAB2, GRB2-associated binding protein 2; AKT2, v-akt murine thymoma viral oncogene homolog 2; VDAC, voltage-dependent anion channel; SOX4, SRY (sex-determining region Y)-box 4; SLC7A11, solute carrier family 7 member 11; IGFR1, insulin-like growth factor 1 receptor; TGF-β, transforming growth factor-beta; CD73, cluster of differentiation 73; RFVT3, known as SLC52A3 (solute carrier family 52 member 3); PTP4A1, protein tyrosine phosphatase 4a1.*

## **Table 1.**

*Simplified list of diagnostic miRNA markers for colorectal cancer (modified from Refs. [58, 59]).*

hence, expression levels of miR-125p are associated with poor survival among CRC patients [69]. However, miR34 expression is a good prognostic marker. miR-34 is one of the targets of p53 protein and it increases miRNA expression. miR-34 then suppresses the expression of WNT pathway and epithelial mesenchymal transition (EMT)-related genes. Increase of miR-34b and miR-34c levels in stromal tissue is

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

high mortality risk [83].

these resistance mechanisms [87, 88].

*4.3.1 Chemotherapy*

leading to poor prognosis in colon cancer [70–72]. miR-122, miR-214, miR-372, miR-15b, let-7e, and miR-17 are other dysregulated miRNAs found in *TP53* mutated tumors [73]. miR-148-b and miR-221 are also important diagnostic markers associated with *p53* mutational status, and their overexpression is associated with worse prognosis [74, 75]. miR-143 and miR-145 are frequently downregulated in CRC and their one of the targets is KRAS mRNA; hence, they are important prognostic and predictive biomarkers in CRC [76, 77]. Let-7 role is one of the well-studied tumor suppressor miRNAs, which targets RAS. Let-7a expression is higher in *KRAS* mutated metastatic samples than normal mucosa or nonmetastatic disease [78]. Decrease Let-7b expression is worse prognostic marker, which is associated with recurrence and low overall survival of patients [79]. Furthermore, decrease in miR-487b levels is associated with liver metastasis in CRC patients [80]. Not only KRASassociated miRNAs act as tumor suppressor, some of them are acting oncogenic in prognosis. miR-200 and miR-221 are downstream miRNAs of RAS pathway, and

high expression of these miRNAs is related with worse prognosis [81].

**4.3 miRNAs in treatment response prediction of colorectal cancer**

Furthermore, exosome-containing miRNAs (miR-17/92 cluster and miR-19a cluster) are evaluated as biomarkers for early diagnosis and high recurrence in patients with CRC [82]. miR-21-5p, miR-29-3p, and miR-148-3p levels were studied in CRC samples and show that dysregulation in these miRNAs is associated with

A variety of therapeutic advances are existed for CRC treatment such as conventional chemotherapy (5-fluorouracil, capecitabine, irinotecan, oxaliplatin), immunotherapy, radiotherapy, and chemoradiotherapy. miRNAs play an important role in the regulation of effectiveness and resistance to these therapies and prediction of personalized therapy response [84, 85]. Resistance to therapy is still the biggest challenge for defeating cancer. It may be caused by a variety of reasons such as reduction in transportation and intracellular accumulation of drugs by modulating the activity of drug transporters such ATP-binding cassette subfamily B (ABCB)/multidrug resistance (MDR) transporters (which is reviewed in reference [86]), dysregulation in DNA damage repair mechanisms, insufficient or oncogenic immune response, blockage of apoptosis, emergence of inflammation, and altered expression of oncogenes and tumor suppressor genes related with therapy response. miRNAs are actively participating in all of

Although there are advances in cytotoxic and targeted therapy in CRC, drug resistance is one of the most important obstacles in front of successful chemotherapy [89]. Fluoropyrimidine-based chemotherapy (5-FU or capecitabine), vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR)-targeted, and epidermal growth factor receptor (EGFR)-targeted therapies are the main therapeutic methods for CRC [87]. miRNAs have role in chemotherapy resistance in terms of deregulation of drug metabolism-related enzymes, increased efflux of chemotherapeutics, impairment of chemotherapeutic-induced

miR-92b-3p, miR-3156-5p, miR-10a-5p, and miR-125a-5 were found to be related with progression-free survival in meta;static CRC patients treated with 5-FU/oxaliplatin/bevacizumab regime [90]. A negative relationship was found between miR-27b, miR-148a, and miR-326 expression levels and progression-free

apoptosis, modulation of DNA damage repair, and autophagy [87].
