CCDC12 promotes tumor development and invasion through the Snail pathway in colon adenocarcinoma

Fengying Du,Leping Li,Kangdi Dong,Qiang Wang,Hongqing Zhuo,Lipan Peng,Jizhun Zhang,Changqing Jing,Wenting Pei,Tao Xu

doi:10.1038/s41419-022-04617-y

Abstract

Integrative expression Quantitative Trait Loci (eQTL) analysis found that rs8180040 was significantly associated with Coiled-coil domain containing 12 (CCDC12) in colon adenocarcinoma (COAD) patients. Immunohistochemical staining and western blotting confirmed CCDC12 was highly expressed in COAD tissues, which was consistent with RNA-Seq data from the TCGA database. Knockdown of CCDC12 could significantly reduce proliferation, migration, invasion, and tumorigenicity of colon cancer cells, while exogenous overexpression of CCDC12 had the opposite effect. Four plex Isobaric Tags for Relative and Absolute Quantitation assays were performed to determine its function and potential regulatory mechanism and demonstrated that overexpression of CCDC12 would change proteins on the adherens junction pathway. Overexpressed Snail and knocked down CCDC12 subsequently in SW480 cells, and we found that overexpression of Snail did not significantly change CCDC12 levels in SW480 cells, while knockdown of CCDC12 reduced that of Snail. CCDC12 plays a significant role in tumorigenesis, development, and invasion of COAD and may affect the epithelial to mesenchymal transformation process of colon cancer cells by regulating the Snail pathway.

Highlights

The incidence of colon cancer is the fifth-highest for malignant tumors, with over one million new colon cancer patients worldwide each year [1]
Knockdown of coiled-coil domain containing 12 (CCDC12) inhibits tumor proliferation, migration, invasion, and promoted apoptosis Through real-time quantitative polymerase chain reaction (RT-qPCR) with 5 different colon cancer cell lines and the CCD18Co as the control, we found CCDC12 was relatively overexpressed in LOVO and SW480 cell lines (Fig. S1), we reduced their expression levels using sh-CCDC12 RNA
Number of cancer nodules on the liver of mice was reduced, and IHC showed that the expression of CCDC12 was downregulated (Fig. 2H). All these results indicated that knockdown of CCDC12 could effectively inhibit colon cancer cell proliferation, invasion, migration, and promote apoptosis in vivo and in vitro, which was related to epithelial to mesenchymal transformation (EMT)

Summary

INTRODUCTION

The incidence of colon cancer is the fifth-highest for malignant tumors, with over one million new colon cancer patients worldwide each year [1]. Refractory and metastatic colon adenocarcinoma (COAD) has been a major problem worldwide [4,5,6]. CCDC106 is related to the progression and poor prognosis of non-small cell lung cancer [10], and CCDC67 has been demonstrated to inhibit the proliferation of papillary thyroid carcinomas [11]. A genome-wide association study (GWAS) identified colorectal cancer risk single nucleotide polymorphism (SNP) rs1076394 as an expression Quantitative Trait Loci (eQTL) for CCDC12 [12]. We demonstrated that high expression levels of CCDC12 in COAD were closely associated with tumor development and aggression. CCDC12 promoted COAD tumor cell proliferation, invasion, migration, and inhibited apoptosis in in vitro and in vivo experiments. Our study demonstrated a biological link between CCDC12 and COAD, which could be used as a potential therapeutic target

RESULTS

Du et al 2

DISCUSSION

CONFLICT OF INTEREST