Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Feb 15, 2025; 17(2): 92437
Published online Feb 15, 2025. doi: 10.4251/wjgo.v17.i2.92437
Unveiling expression patterns, mechanisms, and therapeutic opportunities of transmembrane protein 106C: From pan-cancers to hepatocellular carcinoma
Jian-Di Li, Rong-Quan He, Yi-Wu Dang, Zhi-Guang Huang, Dan-Dan Xiong, Lu Zhang, Xiu-Fang Du, Gang Chen
Jian-Di Li, Yi-Wu Dang, Zhi-Guang Huang, Dan-Dan Xiong, Lu Zhang, Xiu-Fang Du, Gang Chen, Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Rong-Quan He, Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Author contributions: Chen G, He RQ, and Dang YW designed the study, supervised the experiments, and polished the manuscript; Li JD collected the transcriptomic data, performed all computational biological analyses, and drafted the manuscript; Huang ZG and Xiong DD performed the cellular and xenograft experiments; Zhang L and Du XF contributed to the collection of clinical samples; All authors read and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. NSFC82160762, No. NSFC82460783; Natural Science Foundation of Guangxi, No. 2022GXNSFBA035657; and Innovation Project of Guangxi Graduate Education, No. JGY2023068, No. YCSW2023220.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University, No. 2021-KY-Guoji-054.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Laboratory Animal Ethics Committee of Guangxi Medical University.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: The datasets analyzed in this study are available in the open access repositories in Supplementary Table 1. Further inquiries can be directed to the corresponding author.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Gang Chen, PhD, Professor, Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, No. 22 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, China. chengang@gxmu.edu.cn
Received: January 25, 2024
Revised: September 30, 2024
Accepted: November 22, 2024
Published online: February 15, 2025
Processing time: 358 Days and 14.7 Hours
Abstract
BACKGROUND

Although transmembrane protein 106C (TMEM106C) has been elucidated to be overexpressed in cancers, its underlying mechanisms have not yet been fully understood.

AIM

To investigate the expression levels and molecular mechanisms of TMEM106C across 34 different cancer types, including liver hepatocellular carcinoma (LIHC).

METHODS

We analyzed TMEM106C expression patterns in pan-cancers using microenvironment cell populations counter to evaluate its association with the tumor microenvironment. Gene set enrichment analysis was conducted to identify molecular pathways related to TMEM106C. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) analysis was conducted to identify upstream transcriptional regulators of TMEM106C. In LIHC, we examined mRNA profiles, performed in-house quantitative polymerase chain reaction, immunohistochemistry, and constructed a co-expression gene network. Functional assays, including cell counting kit-8, cell cycle, apoptosis, migration, and invasion, were conducted. The effect of nitidine chloride (NC) on LIHC xenograft was evaluated through RNA sequencing and molecular docking. Finally, potential therapeutic agents targeting TMEM106C were predicted.

RESULTS

TMEM106C was significantly overexpressed in 27 different cancer types and presaged poor prognosis in four of these types, including LIHC. Across pan-cancers, TMEM106C was inversely correlated to the abundances of immune and stromal cells. Furthermore, TMEM106C was significantly linked to cell cycle and DNA replication pathways in pan-cancers. ChIP-seq analysis predicted CCCTC-binding factor as a pivotal transcriptional factor targeting the TMEM106C gene in pan-cancers. Integrated analysis showed that TMEM106C was upregulated in 4657 LIHC compared with 3652 normal liver tissue [combined standardized mean difference = 1.31 (1.09, 1.52)]. In-house LIHC samples verified the expression status of TMEM106C. Higher TMEM106C expression signified worse survival conditions in LIHC patients treated with sorafenib, a tyrosine kinase inhibitor (TKI). Co-expressed analysis revealed that TMEM106C were significantly enriched in the cell cycle pathway. Knockout experiments demonstrated that TMEM106C plays a crucial role in LIHC cell proliferation, migration, and invasion, with cell cycle arrest occurring at the DNA synthesis phase, and increased apoptosis. Notably, TMEM106C upregulation was attenuated by NC treatment. Finally, TMEM106C expression levels were significantly correlated with the drug sensitivity of anti-hepatocellular carcinoma agents, including JNJ-42756493, a TKI agent.

CONCLUSION

Overexpressed TMEM106C was predicted as an oncogene in pan-cancers, which may serve as a promising therapeutic target for various cancers, including LIHC. Targeting TMEM106C could potentially offer a novel direction in overcoming TKI resistance specifically in LIHC. Future research directions include in-depth experimental validation and exploration of TMEM106C’s role in other cancer types.

Keywords: Transmembrane protein 106C; Pan-cancers; Liver hepatocellular carcinoma; Molecular biology; Nitidine chloride

Core Tip: Herein, we conducted the first study to investigate the expression implications, immune associations, and transcriptional regulatory mechanisms of transmembrane protein 106C (TMEM106C) across 34 cancer types, including liver hepatocellular carcinoma (LIHC). Our multicenter study represents the largest investigation to date of the expression pattern and biological functions of TMEM106C in LIHC. Of particular note, our study discovered the inhibitory effect of nitidine chloride on TMEM106C overexpression, which has not been reported previously.