Autophagy-Related Signatures as Prognostic Indicators for Hepatocellular Carcinoma

Wen Ye; Zhehao Shi; Yilin Zhou; Zhongjing Zhang; Yi Zhou; Bicheng Chen; Qiyu Zhang

doi:10.3389/fonc.2022.654449

Autophagy-Related Signatures as Prognostic Indicators for Hepatocellular Carcinoma

Front Oncol. 2022 Mar 24:12:654449. doi: 10.3389/fonc.2022.654449. eCollection 2022.

Authors

Wen Ye¹, Zhehao Shi², Yilin Zhou³, Zhongjing Zhang², Yi Zhou², Bicheng Chen⁴, Qiyu Zhang²

Affiliations

¹ Department of Breast Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
² Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
³ College of Engineering, Boston University, Boston, MA, United States.
⁴ Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.

Abstract

Background: Hepatocellular carcinoma (HCC) is the most common and deadly type of liver cancer. Autophagy is the process of transporting damaged or aging cellular components into lysosomes for digestion and degradation. Accumulating evidence implies that autophagy is a key factor in tumor progression. The aim of this study was to determine a panel of novel autophagy-related prognostic markers for liver cancer.

Methods: We conducted a comprehensive analysis of autophagy-related gene (ARG) expression profiles and corresponding clinical information based on The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. The univariate Cox proportional regression model was used to screen candidate autophagy-related prognostic genes. In addition, a multivariate Cox proportional regression model was used to identify five key prognostic autophagy-related genes (ATIC, BAX, BIRC5, CAPNS1, and FKBP1A), which were used to construct a prognostic signature. Real-time qPCR analysis was used to evaluate the expression levels of ARGs in 20 surgically resected HCC samples and matched tumor-adjacent normal tissue samples. In addition, the effect of FKBP1A on autophagy and tumor progression was determined by performing in vitro and in vivo experiments.

Results: Based on the prognostic signature, patients with liver cancer were significantly divided into high-risk and low-risk groups in terms of overall survival (OS). A subsequent multivariate Cox regression analysis indicated that the prognostic signature remained an independent prognostic factor for OS. The prognostic signature possessing a better area under the curve (AUC) displayed better performance in predicting the survival of patients with HCC than other clinical parameters. Furthermore, FKBP1A was overexpressed in HCC tissues, and knockdown of FKBP1A impaired cell proliferation, migration, and invasion through the PI3K/AKT/mTOR signaling pathway.

Conclusion: This study provides a prospective biomarker for monitoring outcomes of patients with HCC.

Keywords: FKBP1A; HCC (hepatic cellular carcinoma); ICGC; TCGA; autophagy; prognostic signature.