Association analysis of miRNA-related genetic polymorphisms in miR-143/145 and KRAS with colorectal cancer susceptibility and survival

Abstract

Background MicroRNAs have important roles in tumorigenesis. There is accumulating evidence of aberrant expression of miR-143 and miR-145 and their target gene KRAS has been described in colorectal cancer (CRC). We hypothesize that single nucleotide polymorphisms (SNPs) within or near mRNA-miRNA binding sites may affect miRNA/target gene interaction, resulting in differential mRNA/protein expression and promoting the development and progression of CRC.Methods We conducted a case-control study of 507 CRC cases recruited from a tertiary hospital and 497 population-based controls to assess the association of genetic polymorphisms in miR-143/145 and the KRAS 3′ untranslated region (3′ UTR) with CRC susceptibility and survival. Deaths and causes of death among the CRC cases were identified using the Hangzhou Cancer Registration System and Death Surveillance System. Genetic variations of genomic regions located from 500 bp upstream to 500 bp downstream of the miR-143/miR-145 gene and the 3′ UTR of KRAS were selected using the Haploview and HaploReg software. Results Using publicly available expression profiling data, we found that miR-143/145 and KRAS expression were all reduced in rectal cancer tissue compared with adjacent normal mucosa. The Rs74693964 C/T variant located 65 bp downstream of miR-145 genomic regions was observed to be associated with CRC susceptibility (adjusted odds ratio 2.414, 95% CI: 1.385–4.206). Among non-smokers, the miR-143 rs41291957 GA genotype and miR-145 rs74693964 CT genotype were borderline significantly associated with an increased risk of rectal cancer. However, there was no interaction effect between selected SNPs and smoking status. Cumulative effects of miR-143 and miR-145 on CRC risk were observed (Ptrend=0.03). CRC cases carrying variant genotype TT of KRAS rs712 had poorer survival (log-rank P=0.044, adjusted hazard ratio 4.328, 95% CI: 1.236–15.147). Conclusions Our results indicate that miRNA-related polymorphisms in miR-143/145 and KRAS are likely to be deleterious and represent potential biomarkers for CRC susceptibility and survival.

Study of microRNA expression profiling as biomarkers for colorectal cancer patients in Lebanon

“…Furthermore, miR-145 is downregulated in CRC tissue and induces tumorigenesis by acting on its target, Kirsten rat sarcoma viral oncogene homolog (41). Consistent with the present results, the upregulation of miR-31 and downregulation of miR-145 have been reported in CRC tissue in different populations such as the Chinese, Japanese and European populations (38,42,43).…”

“…miRNA expression varies within populations primarily due to specific genetic variation and single nucleotide polymorphism in mature miRNA (35,36). The present study assessed the expression profile of miRNAs (miR-31, miR-145, In CRC, dysregulation of miR-31 and miR-145 have been implicated in cell proliferation, invasion and migration in vitro and in tumorigenesis and metastasis in CRC tissue (37,38). miR-31 is reported to be upregulated in CRC tissue suppressing Special AT-rich sequence-binding protein 2 gene and regulating v-Raf murine sarcoma viral oncogene homolog B activation, serving a role in the signaling pathway downstream of epidermal growth factor receptor (39,40).…”

Fusobacterium nucleatum induces excess methyltransferase‐like 3‐mediated microRNA‐4717‐3p maturation to promote colorectal cancer cell proliferation

“…[15][16][17] For example, miR-143 and miR-145 were consistently downregulated in CRC tumor tissues of different stages relative to normal colonic mucosal tissues. 18 In contrast, other miRNAs (miR-21, miR-29a, miR-92a, and miR-135b) are reportedly upregulated in CRC patient tumor tissues. 7,[19][20][21] A growing body of evidence further suggests that F. nucleatum is linked to CRC onset, progression, and metastasis, with this bacterial infection potentially altering miRNA expression in the context of CRC progression.…”

“…Recently, miRNAs have emerged as valuable diagnostic biomarkers for CRC 15–17 . For example, miR‐143 and miR‐145 were consistently downregulated in CRC tumor tissues of different stages relative to normal colonic mucosal tissues 18 . In contrast, other miRNAs (miR‐21, miR‐29a, miR‐92a, and miR‐135b) are reportedly upregulated in CRC patient tumor tissues 7,19–21 .…”

Dysregulated miRNAs network in the critical COVID-19: An important clue for uncontrolled immunothrombosis/thromboinflammation

“…The existence of the A/T allele of miR-SNP rs767649 (located in the regulation region of the miR-155 gene) can underlie the elevated transcriptional activity of this gene [183] , [242] , [243] , [244] , [245] , [246] , [247] ( Table 1 ). Moreover, the reduced expressions of miR-143 and miR-145 have respectively been reported in the carriers of CT/TT variant of miR-SNP rs353292 (located 673 bp upstream from the start site) and C/T variant of miR-SNP rs74693964 (located 65 bp downstream of the miR-145 genomic region) [248] , [249] ( Table 1 ). Accordingly, the presence of the miR-SNPs in patients with the critical COVID-19 can be followed by the disrupted functions of these miRNAs ( Table 1 ).…”