*4.3.2 Immunotherapy*

Since chemo/radio therapies and surgery have limitations, immunotherapy is a good alternative to treat CRC patients. Immunotherapy aimed to evoke immune system to eliminate tumors either using immune stimulatory cytokines (vaccines, etc.) or checkpoint inhibitors [such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death 1 (PD-1) receptor, and its ligands (PD-L1/2)] [92]. Interestingly, immune cell filtrates more in MSI-high CRC, and these subtypes are responding better to immunotherapies [93].


*Abbreviations: 5-FU, 5-fluorouracil; EGFR, epidermal growth factor; RAF-1, Raf protooncogene; BNIP2, BCL2 interacting protein 2; MSH2, human mutS homolog 2; BTG-1, BTG antiproliferation factor 1; APAF-1, apoptotic peptidase-activating factor 1; ABCF-1, ATP-binding cassette subfamily D member 1; DPYD, dihydropyrimidine dehydrogenase; Bcl-2, B cell lymphoma-2; IGF-1R, insulin-like growth factor 1 receptor; FOXO3a, forkhead box class O3; PHLPP1, Phlpp1 PH domain and leucine-rich repeat protein; TYMS, thymidylate synthase; ATM, ataxia telangiectasia mutated; HMGA2, high mobility group AT-hook 2; BIRC5, baculoviral IAP repeat containing 5; MRP8, myeloid-related protein 8; ABCG2, ATP-binding cassette subfamily G member 2; P21, cyclin-dependent kinase inhibitor 1A.*

### **Table 2.**

*The expression profile of miRNAs that have role on chemotherapy response in colorectal cancer (modified from Ref. [85]).*

**39**

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

activation of tumor-infiltrating CD8<sup>+</sup>

tion of outcome responses of patients [97].

radiotherapy/radiochemotherapy prediction.

**5. Concluding remarks and limitations**

apoptosis of CD8<sup>+</sup>

for CRC treatment [96].

*4.3.3 Potential candidates*

miRNAs are essential in regulation of the immune response as well. The role of miR-34 has been mentioned earlier. Upregulation of miR-34a elicits the

are also involved in innate immunity by macrophages and NK cells, and adaptive immunity by B cells, T cells, and dendritic cells. miR-124 modulates signal transducer and activator of transcription 3 (STAT3) pathway and enhances the T cell-mediated immune clearance [95]. miR-491 regulates the proliferation and

and promotes its apoptosis via targeting B-cell lymphoma-extra-large (Bcl-xL), cyclin-dependent kinase-4 (CDK4), and T cell factor 1 (TCF1), hence aiding tumor cells escaping from immune system. Tumor-derived TGF-β also induces the miR-491 expression. Thus, miR-491 can be evaluated as a new immunotarget

miR-196b, miR-378a, and miR-486-5p are evaluated as predictive biomarkers for the efficacy of the vaccine treatment in CRC [97]. miRNAs were enrolled in Phase II studies. In 16 patients, high expression of miR-196b-5p and low expression of miR-378a-3p and miR-486-5p are associated with better prognosis after vaccine treatment. Hence, these miRNAs can be determined as novel biomarkers for predic-

miRNAs are also involving in radiotherapy responses. The expression of miRNAprocessing enzymes Drosha and Dicer was found to be upregulated in radioresistant cell lines when compared with radiosensitive cell lines [98]. The role of miRNAs in radiotherapy response was evaluated further in the study cited as reference [87]. In the study, biomarkers for the prediction of chemoradiotherapy response in CRC were identified by using integrative and systematic bioinformatics analysis. The unique target genes of miR-198 and miR-765 were altered significantly upon transfection of specific miRNA mimics in the radiosensitive cell line. Thus, it could be said that miR-198, miR-202, miR-371-5p, miR-513a-5p, miR-575, miR-630, and miR-765 could be used for predicting the response of CRC to preoperative chemoradiotherapy [87]. Still, further studies are needed to understand the miRNA role in

By the discovery of miRNAs, a significant number of studies have been conducted to indicate the utility of miRNAs. According to the highlighted studies, miRNAs in body fluids have potential to be predictive, diagnostic or prognostic biomarkers; and also they can be therapeutic targets due to their inducer ability on tumorigenesis. Basically, miRNAs offer promising practice for screening, diagnosis, prognosis, and treatment of cancer. Therefore, these noncoding RNA fragments may be used alone or combined with other protocols to screen, diagnose, prognose, and treat cancer. However, their clinical importance is still not conclusive, and

Evidences showed that inhibition of oncomiRs or replacement of tumor suppressive miRNAs could be used to develop innovative treatment approaches. Further studies are needed to reveal the molecular mechanisms on the regulation of miRNA biogenesis. Determination of miRNA target genes, molecular interactions between target mRNA and miRNAs, and signaling pathways will help to interpret molecular mechanisms of cancer. Besides investigations on miRNA expression patterns and

validation studies are needed for routine-based clinical application.

T cells [96]. miR-491 inhibits the activation of CD8<sup>+</sup>

T cells by targeting PD-L1 [94]. miRNAs

T cells
