Case Control Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Aug 6, 2022; 10(22): 7686-7697
Published online Aug 6, 2022. doi: 10.12998/wjcc.v10.i22.7686
Comprehensive proteomic signature and identification of CDKN2A as a promising prognostic biomarker and therapeutic target of colorectal cancer
Qian-Qian Wang, Yuan-Chen Zhou, Yu-Jia Zhou Ge, Geng Qin, Teng-Fei Yin, Dong-Yan Zhao, Chang Tan, Shu-Kun Yao
Qian-Qian Wang, Yuan-Chen Zhou, Graduate School, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 10029, China
Yu-Jia Zhou Ge, Dong-Yan Zhao, Graduate School, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
Geng Qin, Shu-Kun Yao, Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China
Teng-Fei Yin, Chang Tan, Graduate School, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
Author contributions: Wang QQ performed the study, analyzed the data, and drafted the manuscript; Zhou YC and Zhou Ge JY collected samples from subjects; Qin G provided guidance on experimental procedures; Yin TF, Zhao DY, and Tan C collected the clinical data; Yao SK supervised the study performance, revised the manuscript, and obtained the funding; and All authors read and approved the final manuscript.
Supported by National Key Development Plan for Precision Medicine Research, No. 2017YFC0910002.
Institutional review board statement: This study was approved by the Ethics Committee of China-Japan Friendship Hospital (No. 2018-116-K85).
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: All authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement, and the manuscript was prepared and revised according to the STROBE Statement.
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: Shu-Kun Yao, MD, PhD, Professor, Department of Gastroenterology, China-Japan Friendship Hospital, No. 2 Yinghua East Road, Chaoyang District, Beijing 100029, China. shukunyao@126.com
Received: March 17, 2022
Peer-review started: March 17, 2022
First decision: May 12, 2022
Revised: May 19, 2022
Accepted: June 22, 2022
Article in press: June 22, 2022
Published online: August 6, 2022
Abstract
BACKGROUND

The carcinogenesis of colorectal cancer (CRC) involves many different molecules and multiple pathways, and the specific mechanism has not been elucidated until now. Existing studies on the proteomic signature profiles of CRC are relatively limited. Therefore, we herein aimed to provide a more comprehensive proteomic signature profile and discover new prognostic markers and therapeutic targets by performing proteomic analysis of CRC and paired normal tissues.

AIM

To investigate the proteomic signature and identify novel protein prognostic biomarkers of CRC.

METHODS

Cancer tissues and paired normal tissues were collected from 48 patients who underwent surgical removal at the China-Japan Friendship Hospital from January 2020 to June 2021. Data independent acquisition (DIA) quantitative proteomic analysis was performed using high-performance liquid chromatography–mass spectrometry/mass spectrometry (nano-UHPLC–MS/MS) to identify differentially expressed proteins, among which those with a P adj value (t test, BH correction) < 0.05 and an absolute fold change (|log2FC|) > 2 were identified as potential markers. Differentially expressed proteins were selected by bioinformatics analysis and validated by immunohistochemical tissue microarrays, and their association with prognosis was further analyzed with the Gene Expression Profiling Interactive Analysis database to identify prognostic protein biomarkers of CRC.

RESULTS

Significantly differential protein expression was observed between cancer tissues and normal tissues. Compared with normal tissues, 1115 proteins were upregulated and 705 proteins were downregulated in CRC based on P adj < 0.05 and |log2FC| > 2, and bioinformatics analysis revealed that the differentially expressed proteins were involved in multiple biological processes associated with tumorigenesis, including ribosome biogenesis in eukaryotes, focal adhesion, extracellular matrix-receptor interactions and other tumor metabolism processes. Moreover, cyclin-dependent kinase inhibitor 2A (CDKN2A) expression was markedly upregulated in CRC, as validated by immunohistochemistry (0.228 vs 0.364, P = 0.0044), and was significantly enriched in tumor proliferation and signal transduction pathways such as the cell cycle and p53 signaling pathways. High CDKN2A expression was significantly correlated with poor prognosis (P = 0.021). These results demonstrated that CDKN2A functions as a driver of CRC.

CONCLUSION

Our study provides a comprehensive proteomic signature of CRC and highlights CDKN2A as a potential powerful prognostic marker and precision therapeutic target.

Keywords: Colorectal cancer, Proteomic analysis, Cyclin-dependent kinase inhibitor 2A, Prognostic biomarker, Therapeutic target, Precision treatment

Core Tip: In this study, quantitative proteomic analysis of colorectal cancer (CRC) was comprehensively performed, revealing many differentially expressed proteins that may be useful for mining novel targets. The results revealed the overexpression of thousands of tumor proteins, among which cyclin-dependent kinase inhibitor 2A (CDKN2A) was the highlight of this study, and high CDKN2A expression in CRC was significantly associated with poor prognosis and could serve as a powerful prognostic marker and precision therapeutic target.