The immune-related objective response rate and immune-related PFS rate were 40% and 78%, respectively, for MSI-H CRCs and 0% and 11% in MSS CRCs [46,47]. might serve as predictive biomarker in this setting [7]. In another study, forced expression of miR-21 significantly inhibited Thymosin β4 apoptosis and increased cell growth, invasion and resistance of tumor cells to chemotherapeutic agent 5-FU and radiation [8]. Moreover, miR-21 might indirectly regulate the expression of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD), enzymes involved in metabolism of fluoropyrimidines [8]. Valeri et al. demonstrated that miR-21 downregulates human mutS homolog 2 (hMSH2) and 6 (hMSH6), which are the core mismatch repair (MMR) proteins. Furthermore, xenograft studies confirmed that miR-21 overexpression reduces the therapeutic efficacy of 5-FU. These findings suggest that silencing miR-21 could restore the sensibility of CRC cells to 5-FU [9]. Moreover, downregulation of other miRNAs was associated with chemoresistance. Karaayvaz et al. showed in 22 pair of fresh-frozen controls and CRC patients that miR-129 level was significantly decreased in tumor tissues compared with normal settings ( 0.0001) and in another set of 61 FFPE CRCs the manifestation of miR-129 was significantly reduced in individuals with stage 3 and stage 4 disease compared with both normal or adenoma cells ( 0.0001) [8]. This miRNA improved the cytotoxic effect of 5-FU both in vitro and in vivo and suggest a potential of developing miR-129-centered therapeutic strategies to enhance or conquer the resistance to 5-FU in CRC [10]. Dong et Thymosin β4 al. observed that miR-429 manifestation is correlated with increased malignant potential, poor prognosis and chemosensitivity. In particular, miR-429 manifestation was significantly improved in CRC main tissue compared with adjacent normal cells ( 0.0001) and in CRC Thymosin β4 individuals serum vs. healthy subjects ( 0.0001). In addition, miR-429 manifestation was positively correlated with TNM stage, lymph node metastasis, distant metastasis and tumor size (= 0.00001, = 0.0001, = 0.00001 and = 0.036 respectively). KaplanCMeier analysis on these individuals indicated that subjects with high manifestation of miR-429 were associated with shorter overall survival compared with the low expressing CRC individuals (= 0.0021). Moreover, miR-429 overexpression was associated with poor response to 5-FU-based chemotherapy in individuals with CRC ( 0.001) [11]. Another study observed that 5-FU-resistant CRC cells display elevated levels of miR-577. Heat shock protein 27 (HSP27) was identified as a target gene of miR-577. Interestingly, enforced manifestation of HSP27 modulated the effects of miR-577 on 5-FU level of sensitivity in CRC cells [12]. A study of Xu et al. observed that miR-1915 could play a role in the development of multidrug resistance in CRC cells by modulation of apoptosis though Bcl-2 [13]. The authors found that improved levels of miR-1915 in the mimics-transfected HCT116/L-OHP cells decreased Bcl-2 protein level and sensitized CRC cells to several anticancer medicines. In another study, it was found that miR-122 was in a different way indicated between 5-FU resistant and sensitive CRC cells. Overexpression of miR-122 in 5-FU-resistant cells resensitizes 5-FU resistance through the inhibition of glycolytic enzyme pyruvate kinase type M2 (PKM2) both in vitro and in vivo [14]. To et al. investigated the manifestation of an efflux transporter, ABCG2, in CRC and normal colonic mucosa [15]. In this study, carried out on 12 CRC individuals and 2 polyp samples, miR-203 was found to be downregulated in CRC specimens in comparison to normal colon mucosa. Downregulation of miR-203 induced ABCG2 promoter methylation, through its target DNA methyltransferase DNMT3b activation, and a significant reduction in ABCG2 manifestation. CRC tumors have a significantly lower ABCG2 manifestation than the adjacent normal colon cells. Downregulation of miR-203 in CRC caused ABCG2 promoter methylation and significantly lower ABCG2 manifestation in CRC. Therefore, the repair of ABCG2 function via modulating this fresh miRNA-methylation mechanism might represent a good strategy in CRC prevention and treatment [8]. Lopes-Ramos et al. analyzed miRNA manifestation profile in rectal tumor biopsies prior to neoadjuvant chemoradiotherapy (nCRT) and found four miRNAs differentially indicated in individuals who obtained total or incomplete response ( 0.0001): in particular three miRNAs were overexpressed in complete responders (miR-21-5p, miR-1246, and miR-1290-3p) and one, miR-205-5p, was overexpressed in incomplete responders [16]. Moreover, in rectal malignancy individuals who obtained the complete response, overexpression of miR-21-5p was observed. Interestingly, inside a subset of individuals with total response after nCRT with early local recurrence was characterized by downregulation of miR-21-5p, related to that in incomplete responders [16]. The same establishing of individuals affected by rectal malignancy who underwent the nCRT were analyzed also by Carams et al. [17]. The authors found that the majority of pre-treatment biopsies (78% of instances) are characterized by miR-21 overexpression, which also correlate having a worse response after nCRT (= 0.013). Level of sensitivity, specificity, bad predictive ideals, and positive predictive value were 86.6%, 60%, 42.8%, SQLE and 92%, respectively. Moreover, multivariate analysis confirmed the clinical significance of miR-21.
The immune-related objective response rate and immune-related PFS rate were 40% and 78%, respectively, for MSI-H CRCs and 0% and 11% in MSS CRCs [46,47]