Identification of potential prognostic biomarkers among gene models for coiled-coil domain-containing family members in hepatocellular carcinoma elucidates their influence on the hypoxia pathway and immune microenvironment

Jing Li; Dafang Zhang; Hao Liu; Danhua Wang; Chunxiao Pan; Tiago Biachi de Castria; Shaffer R S Mok; Zegao Zhou; Changqing Yan

doi:10.21037/jgo-23-652

Identification of potential prognostic biomarkers among gene models for coiled-coil domain-containing family members in hepatocellular carcinoma elucidates their influence on the hypoxia pathway and immune microenvironment

J Gastrointest Oncol. 2023 Dec 31;14(6):2559-2573. doi: 10.21037/jgo-23-652. Epub 2023 Dec 6.

Authors

Jing Li^#¹, Dafang Zhang^#², Hao Liu³, Danhua Wang⁴, Chunxiao Pan⁴, Tiago Biachi de Castria^{5

6}, Shaffer R S Mok⁵, Zegao Zhou³, Changqing Yan³

Affiliations

¹ Department of Oncology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China.
² Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China.
³ Department of General Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
⁴ Burning Rock Biotech, Guangzhou, China.
⁵ Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL, USA.
⁶ Morsani College of Medicine, University of South Florida, Tampa, FL, USA.

^# Contributed equally.

Abstract

Background: The family of coiled-coil domain-containing (CCDC) proteins participates in a wide range of physiological functions and plays a pivotal role in governing the invasion and metastasis of malignant tumor cells. Nonetheless, the precise mechanism governing the interaction among the immune microenvironment, hypoxia pathway, and proliferation in hepatocellular carcinoma (HCC) remains elusive. In this study, our objective was to identify the prognostic significance of CCDC family genes in HCC.

Methods: We conducted an analysis of RNA-seq data from HCC patients sourced from The Cancer Genome Atlas (TCGA) database. Our analysis involved comparing the expression profiles of 168 CCDC family genes between tumor and normal tissues to identify differentially expressed genes (DEGs). The prognostic value of these genes was verified using overall survival (OS) data from TCGA-LIHC patients, employing Univariate and multivariate Cox proportional hazards regression models and Kaplan-Meier plots. Subsequently, we constructed a prognostic signature known as the CCDC score and validated it using additional datasets (ICGC-LIRI-JP and GSE14520). Additionally, we performed functional enrichment analysis and conducted an assessment of the tumor immune microenvironment (TIME).

Results: We identified 34 DEGs of the CCDC family. Among them, six DEGs (CCDC6/22/51/59/132/134) were upregulated and associated with poor prognosis. Higher CCDC score was an independent predictor of poor OS in TCGA-HCC patients (P<0.001, HR =2.37), which was validated in the ICGC-LIRI-JP (P=0.021, HR =2.15) and GSE14520 (P=0.002, HR =2.23) datasets. Functional enrichment analysis showed that hypoxia pathway genes were enriched in the high CCDC score group. Furthermore, immune microenvironment analysis demonstrated that high CCDC score was associated with a suppressed TIME caused by the extrinsic immune escape.

Conclusions: The CCDC score, derived from six CCDC genes, exhibits remarkable expression levels in liver cancer and holds promise as an independent prognostic indicator. Our bioinformatics analysis revealed a high CCDC score is strongly associated with activation of the hypoxia pathway and an immunosuppressive tumor microenvironment in HCC. This profound finding may serve as a cornerstone for innovative targeted drug therapies and pave the way for further investigations into the underlying mechanisms of CCDC-related carcinogenesis in liver cancer.

Keywords: Hepatocellular carcinoma (HCC); coiled-coil domain-containing (CCDC); hypoxia; prognostic model; tumor immune microenvironment (TIME).