Circular RNAs (circRNAs) as a novel type of noncoding RNAs (ncRNAs) are widely studied in the development of human various diseases, including cancer. Here, we found circular RNA hsa_circ_000984 encoded by the CDK6 gene was remarkably upregulated in the tissues of colorectal cancer (CRC) patients and in the CRC cell lines. Moreover, high expression level of hsa_circ_000984 was significantly associated with advanced colorectal cancer. Further analysis revealed that hsa_circ_000984 knockdown could inhibit cell proliferation, migration, invasion in vitro and tumor formation in vivo in CRC cell lines. Mechanically, we found that hsa_circ_000984 may act as a competing endogenous RNA (ceRNA) by competitively binding miR-106b and effectively upregulate the expression of CDK6, thereby inducing a series of malignant phenotypes of tumor cells. Taken together, these observations suggest that the hsa_circ_000984 could mediate the expression of gene CDK6 by acting as a ceRNA, which may contribute to a better understanding of between the regulatory miRNA network and CRC pathogenesis.
Dysregulation of protein synthesis is emerging as a major contributory factor in cancer development. eIF3D (eukaryotic translation initiation factor 3 subunit D) is one member of the eIF3 (eukaryotic translation initiation factor 3) family, which is essential for initiation of protein synthesis in eukaryotic cells. Acquaintance with eIF3D is little since it has been identified as a dispensable subunit of eIF3 complex. Recently, eIF3D was found to embed somatic mutations in human colorectal cancers, indicating its importance for tumour progression. To further probe into its action in colon cancer, we utilized lentivirus-mediated RNA interference to knock down eIF3D expression in one colon cancer cell line HCT116. Knockdown of eIF3D in HCT116 cells significantly inhibited cell proliferation and colony formation in vitro. Flow cytometry analysis indicated that depletion of eIF3D led to cell-cycle arrest in the G2/M phase, and induced an excess accumulation of HCT116 cells in the sub-G1 phase representing apoptotic cells. Signalling pathways responsible for cell growth and apoptosis have also been found altered after eIF3D silencing, such as AMPKα (AMP-activated protein kinase alpha), Bad, PRAS40 [proline-rich Akt (PKB) substrate of 40 kDa], SAPK (stress-activated protein kinase)/JNK (c-Jun N-terminal kinase), GSK3β and PARP [poly(ADP-ribose) polymerase]. Taken together, these findings suggest that eIF3D might play an important role in colon cancer progression.
CD44 as one of the most putative stem cell markers plays a key role in many cellular processes, including cancer cell growth and migration. Functional single nucleotide polymorphisms (SNPs) of CD44 may modulate its gene functions and thus cancer risk. In the current study, we investigated if polymorphisms in the 3’-untranslated region (UTR) of CD44 are associated with increased susceptibility to colorectal cancer (CRC) by conducting a case-control study of 946 CRC patients and 989 cancer-free controls. Three polymorphisms (rs13347C/T, rs10836347C/T, rs11821102G/A) in the 3’-UTR of CD44 were genotyped. We found that the variant genotypes (CT and TT) of rs13347 (adjusted odds ratio (OR)=1.79, 95% confidence interval (CI)=1.50-2.17) increased an individual’s susceptibility to CRC, compared with rs13347CC homozygous genotypes. We also found that CRC patients with the CT/TT genotype had a 1.6-fold increased risk for developing advanced (stage III + IV) CRC. Furthermore, functional assays showed that the C to T base change at rs13347C/T disrupts the binding site for the microRNA hsa-mir-509-3p, thereby increasing CD44 transcriptional activity and expression level. These findings suggest that the rs13347C/T in microRNA binding site may be potential biomarkers for genetic susceptibility to CRC.
The prognostic value of lymphovascular invasion (LVI) in stage I/II colorectal cancer (CRC) does not reach a consensus. To systematically assess prognostic significance of LVI, databases of PubMed, Web of Science, and Embase were searched from inception up to 10 Dec 2016. The pooled hazard ratio (HR) and 95% confidence intervals (CI) were used to determine the prognostic effects. Nineteen relevant studies including 9881 total patients were enrolled. Our results showed that LVI is significantly associated with poor prognosis in overall survival (OS) (HR=2.15, 95 % CI=1.72–2.68, P < 0.01) and disease-free survival (DFS) (HR=1.73, 95% CI=1.50–1.99, P < 0.01), which is similar in stage II patients. Further subgroup analysis revealed that the significance of the association between LVI and worse prognosis in CRC patients is not affected by below factors, including geographic setting, LVI positive rate, treatment, tumor site, and quality of the study. The current meta-analysis suggests that LVI may be a poor prognostic factor for stage I/II CRC patients.
Ubiquitin-proteasome system regulates cell proliferation, apoptosis, angiogenesis, and motility, which are processes with particular importance for carcinogenesis. UBA protein 2-like protein (UBAP2L) was found to be associated with proteasome; however, its biological function is largely unknown. In this study, the mRNA levels of UBAP2L in human normal and colorectal carcinoma tissues were analyzed using the datasets from the publicly available Oncomine database ( www.oncomine.org ) and found UBAP2L was overexpressed in colorectal carcinoma tissues. Furthermore, we elucidated the role of UBAP2L in human colorectal cancer via an RNA interference lentivirus system in three colorectal carcinoma cell lines HCT116, SW1116, and RKO. Knockdown of UBAP2L led to suppressed cell proliferation and impaired colony formation. UBAP2L depletion in HCT116 and RKO cells also induced cell cycle arrest as well as apoptosis. Moreover, the phosphorylation of PRAS40, Bad, and the cleavage of PARP were remarkably increased after UBAP2L knockdown by Intracellular signaling array and also the activation of P38 was obviously decreased and the cleavage of Caspase 3 and Bax were increased after UBAP2L silencing by western blot assay, indicated that UBAP2L might be involved in the cell growth by the regulation of apoptosis-related proteins. Our findings indicated that UBAP2L may be essential for colorectal carcinoma growth and survival. Lentivirus-mediated small interfering RNA against UBAP2L might serve as a potential therapeutic approach for the treatment of colorectal cancer.
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