Circadian gene CSNK1D promoted the progression of hepatocellular carcinoma by activating Wnt/β-catenin pathway via stabilizing Dishevelled Segment Polarity Protein 3

Mengqi Zhu; Jianping Zhang; Saiyan Bian; Xue Zhang; Yiping Shen; Zhiyu Ni; Shiyu Xu; Chun Cheng; Wenjie Zheng

doi:10.1186/s12575-022-00183-x

Circadian gene CSNK1D promoted the progression of hepatocellular carcinoma by activating Wnt/β-catenin pathway via stabilizing Dishevelled Segment Polarity Protein 3

Biol Proced Online. 2022 Dec 2;24(1):21. doi: 10.1186/s12575-022-00183-x.

Authors

Mengqi Zhu^#^{1

2

3}, Jianping Zhang^#^{1

2}, Saiyan Bian^#¹, Xue Zhang¹, Yiping Shen¹, Zhiyu Ni¹, Shiyu Xu¹, Chun Cheng⁴, Wenjie Zheng^{5

6}

Affiliations

¹ Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
² Department of Oncology, Medical School of Nantong University, Affiliated Hospital of Nantong University, Nantong, 226001, China.
³ The First People's Hospital of Xuzhou, Xuzhou, 221000, China.
⁴ Department of Oncology, Medical School of Nantong University, Affiliated Hospital of Nantong University, Nantong, 226001, China. chengchunnt@yeah.com.
⁵ Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China. wenjiezheng@ntu.edu.cn.
⁶ Department of Oncology, Medical School of Nantong University, Affiliated Hospital of Nantong University, Nantong, 226001, China. wenjiezheng@ntu.edu.cn.

^# Contributed equally.

Abstract

Purpose: A variety of studies have connected circadian rhythm to the initiation and progression of hepatocellular carcinoma (HCC). The purpose of this study was to figure out about the circadian genes' profile characteristics, prognostic significance, and targeted values in HCC.

Methods: The expression profiles and prognostic significance of circadian genes in the cancer genome atlas liver hepatocellular carcinoma (TCGA-LIHC) database were investigated using bioinformatics analysis. The expression features of Casein Kinase 1 Delta (CSNK1D), a robust signature gene, was further detected by immunohistochemistry, western blotting and Real-time quantitative PCR (RT-qPCR) in a local HCC cohort. The effect of CSNK1D on corresponding phenotypes of HCC cells was evaluated using Cell Counting Kit-8 (CCK8), flowcytometry, clone assay, Transwell assay, and xenograft assay. In addition, the underlying mechanisms of CSNK1D in the Wnt/β-catenin signaling were validated by multiple molecular experiments.

Results: Abnormal expression of the Circadian genome was associated with the malignant clinicopathological characteristics of HCC patients. A 10 circadian gene-based signature with substantial prognostic significance was developed using Cox regression and least absolute shrinkage and selection operator (LASSO) analysis. Of them, CSNK1D, significantly elevated in a local HCC cohort, was chosen for further investigation. Silencing or overexpression of CSNK1D significantly reduced or increased proliferation, invasion, sorafenib resistance, xenograft development, and epithelial-mesenchymal transformation (EMT) of HCC cells, respectively. Mechanically, CSNK1D exacerbated the aggressiveness of HCC cells by activating Wnt/β-catenin signaling through interacting with Dishevelled Segment Polarity Protein 3 (DVL3).

Conclusions: The Circadian gene CSNK1D was found to contribute to HCC progression by boosting the Wnt/β-catenin pathway, hinting that it could be a prospective therapeutic target for HCC.

Keywords: CSNK1D; DVL3; Hepatocellular carcinoma; Molecular target; Wnt; β-catenin.