Peng T, Sun F, Yang JC, Cai MH, Huai MX, Pan JX, Zhang FY, Xu LM. Novel lactylation-related signature to predict prognosis for pancreatic adenocarcinoma. World J Gastroenterol 2024; 30(19): 2575-2602 [PMID: 38817665 DOI: 10.3748/wjg.v30.i19.2575]
Corresponding Author of This Article
Lei-Ming Xu, MD, PhD, Chief Doctor, Professor, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, No. 1665 Kongjiang Road, Shanghai 200092, China. xuleiming@xinhuamed.com.cn
Research Domain of This Article
Cell Biology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
Tian Peng, Fang Sun, Jia-Chun Yang, Mei-Hong Cai, Man-Xiu Huai, Jia-Xing Pan, Fei-Yu Zhang, Lei-Ming Xu, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200092, China
Co-first authors: Tian Peng and Fang Sun.
Author contributions: Peng T and Sun F contributed equally; Peng T, Sun F and Xu L designed the research; Peng T and Sun F performed the research; Yang J and Cai M contributed new reagents, Huai M and Pan J contributed analytic tools; Peng T, Sun F and Zhang F analyzed the data; Peng T, Sun F and Xu L wrote the paper.
Supported byNational Natural Science Foundation of China, No. 82172737; and Shanghai Science and Technology Development Funds (Shanghai Sailing Program), No. 22YF1427600.
Institutional animal care and use committee statement: The study was reviewed and approved by the Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Approval No. XHEC-F-2023-075).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: Statistical code, and dataset available from the corresponding author at xuleiming@xinhuamed.com.cn. Participants gave informed consent for data sharing.
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: Lei-Ming Xu, MD, PhD, Chief Doctor, Professor, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, No. 1665 Kongjiang Road, Shanghai 200092, China. xuleiming@xinhuamed.com.cn
Received: February 3, 2024 Revised: March 9, 2024 Accepted: April 24, 2024 Published online: May 21, 2024 Processing time: 106 Days and 17.4 Hours
Abstract
BACKGROUND
Lactate, previously considered a metabolic byproduct, is pivotal in cancer progression and maintaining the immunosuppressive tumor microenvironment. Further investigations confirmed that lactate is a primary regulator, introducing recently described post-translational modifications of histone and non-histone proteins, termed lysine lactylation. Pancreatic adenocarcinomas are characterized by increased glycolysis and lactate accumulation. However, our understanding of lactylation-related genes in pancreatic adenocarcinomas remains limited.
AIM
To construct a novel lactylation-related gene signature to predict the survival of patients with pancreatic cancer.
METHODS
RNA-seq and clinical data of pancreatic adenocarcinoma (PDAC) were obtained from the GTEx (Genotype-Tissue Expression) and TCGA (The Cancer Genome Atlas) databases via Xena Explorer, and GSE62452 datasets from GEO. Data on lactylation-related genes were obtained from publicly available sources. Differential expressed genes (DEGs) were acquired by using R package “DESeq2” in R. Univariate COX regression analysis, LASSO Cox and multivariate Cox regressions were produced to construct the lactylation-related prognostic model. Further analyses, including functional enrichment, ESTIMATE, and CIBERSORT, were performed to analyze immune status and treatment responses in patients with pancreatic cancer. PDAC and normal human cell lines were subjected to western blot analysis under lactic acid intervention; two PDAC cell lines with the most pronounced lactylation were selected. Subsequently, RT-PCR was employed to assess the expression of LRGs genes; SLC16A1, which showed the highest expression, was selected for further investigation. SLC16A1-mediated lactylation was analyzed by immunofluorescence, lactate production analysis, colony formation, transwell, and wound healing assays to investigate its role in promoting the proliferation and migration of PDAC cells. In vivo validation was performed using an established tumor model.
RESULTS
In this study, we successfully identified 10 differentially expressed lactylation-related genes (LRGs) with prognostic value. Subsequently, a lactylation-related signature was developed based on five OS-related lactylation-related genes (SLC16A1, HLA-DRB1, KCNN4, KIF23, and HPDL) using Lasso Cox hazard regression analysis. Subsequently, we evaluated the clinical significance of the lactylation-related genes in pancreatic adenocarcinoma. A comprehensive examination of infiltrating immune cells and tumor mutation burden was conducted across different subgroups. Furthermore, we demonstrated that SLC16A1 modulates lactylation in pancreatic cancer cells through lactate transport. Both in vivo and in vitro experiments showed that decreasing SLC16A1 Level and its lactylation significantly inhibited tumor progression, indicating the potential of targeting the SLC16A1/Lactylation-associated signaling pathway as a therapeutic strategy against pancreatic adenocarcinoma.
CONCLUSION
We constructed a novel lactylation-related prognostic signature to predict OS, immune status, and treatment response of patients with pancreatic adenocarcinoma, providing new strategic directions and antitumor immunotherapies.
Core Tip: Our article presents the first study on lactylation modification in pancreatic cancer, establishing a lactylation-related signature that offers new strategic directions for tumor prognosis prediction and combination antitumor immunotherapy. It employs an innovative approach, combining both dry lab and wet lab experimental methods, to validate the genes most closely associated with lactylation.
