Abstract
BackgroundColorectal cancer (CRC) is one of the most frequent malignancy and a leading cause of cancer-related deaths. Therefore, further researches are required to identify novel and more effective diagnoses and to identify molecular targets in treatment of CRC.MethodsC2CD4A expression in CRC tissues and cell lines was detected by qRT-PCR and western blot. The biological functions of C2CD4A were performed both in vitro and in vivo. Western blot, cDNA array, IP-MS, Co-immunoprecipitation assay, and Ubiquitination assay were used to analyze the interaction between C2CD4A and p53. Bioinformatics analysis, FISH, RNA sequencing, luciferase reporter assay, RNA immunoprecipitation, RNA pull-down and rescue experiments, were deployed to detect upstream regulation mechanism of C2CD4A.ResultsC2CD4A was elevated in CRC tissues compared with adjacent normal colorectal tissues. C2CD4A knockdown significantly promoted cell apoptosis and with inhibited proliferation in vitro, and tumorigenicity in vivo, whereas C2CD4A overexpression led to opposite effects. Moreover, circSLC6A6 was upregulated and shown to positively regulate C2CD4A expression via sponging miR-1265. Fundamentally, C2CD4A inhibited p53 signaling pathway through interacting with p53 and increasing its ubiquitination and degradation.ConclusionOur results identified that circSLC6A6/miR-1265/C2CD4A axis, which was involved in CRC via the p53 signaling pathway, may serve as a therapeutic target for CRC.
Highlights
Colorectal cancer (CRC) is one of the most frequent malignancy and a leading cause of cancer-related deaths
Our results identified that circSLC6A6/miR-1265/C2 calcium dependent domain containing 4A (C2CD4A) axis, which was involved in CRC via the p53 signaling pathway, may serve as a therapeutic target for CRC
C2CD4A is frequently upregulated in CRCThrough analysis of the CRC clinical samples from the Cancer Genome Atlas (TCGA) database, there were 461 CRC samples with RNAseq and RNAseqV2 data, in which 50 paired samples were with pathological data and RNAseq data (41 paired samples colon adenocarcinoma samples and 9 paired rectum adenocarcinoma samples)
Summary
Colorectal cancer (CRC) is one of the most frequent malignancy and a leading cause of cancer-related deaths. Further researches are required to identify novel and more effective diagnoses and to identify molecular targets in treatment of CRC. Colorectal cancer (CRC), as one of the most common neoplasms, ranks third most frequently diagnosed cancer for males and second for females and is a leading cause of cancer death worldwide [1]. C2CD4A (C2 calcium dependent domain containing 4A) belongs to the C2CD4 family, which included 3 members, namely C2CD4A, C2CD4B and C2CD4C. Encoded a protein containing a calcium-dependent lazy C2 domain, C2CD4A gene is a nuclear protein with a relative molecular mass of 39KDa. A slice of change in C2 domain coming along with the variation in C2CD4A gene would affect its encoded protein structure and function. There were research gap in C2CD4A’s role in regulating the tumorigenesis of CRC and its mechanism in affecting tumor progression
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