Observational Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jan 15, 2024; 16(1): 118-132
Published online Jan 15, 2024. doi: 10.4251/wjgo.v16.i1.118
Prognostic significance and relationship of SMAD3 phospho-isoforms and VEGFR-1 in gastric cancer: A clinicopathological study
Shi-Lin Lv, Pei Guo, Jun-Rong Zou, Ren-Sheng Chen, Ling-Yu Luo, De-Qiang Huang
Shi-Lin Lv, Ling-Yu Luo, De-Qiang Huang, Hospital of Gastroenterology, Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
Pei Guo, Department of Pathology, Shenzhen Hospital of Southern Medical University, Shenzhen 518000, Guangdong Province, China
Jun-Rong Zou, Institute of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
Ren-Sheng Chen, Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
Author contributions: Huang DQ and Lv SL conceived and designed the study, analyzed and interpreted the data, and wrote the manuscript; Guo P, Zou JR, Luo LY and Chen RS collected clinical samples and completed the related experiments; all authors approved the final manuscript.
Supported by National Nature Science Foundation of China, No. 82060450, No. 82360517, No. 81460374, and No. 31460304; and Nature Science Foundation of Jiangxi Province of China, No. 20232BAB206086, No. 20192BAB205072, No. 20203BBGL73206, No. 2017BCB23086, No. 2017BAB205062, and No. 20181BAB205050.
Institutional review board statement: This study involving patient participants was reviewed and approved by the Ethics Committee of Shanghai Outdo Biotech Company (Shanghai, China) (NO: SHYJS-CP-1801009).
Informed consent statement: Written informed consent was obtained from all participants.
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
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: De-Qiang Huang, MD, Hospital of Gastroenterology, Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, No. 17 Yongwaizen Street, Nanchang 330006, Jiangxi Province, China. hdq0515@ncu.edu.cn
Received: August 4, 2023
Peer-review started: August 4, 2023
First decision: October 23, 2023
Revised: November 20, 2023
Accepted: December 12, 2023
Article in press: December 12, 2023
Published online: January 15, 2024
Abstract
BACKGROUND

The TGF-β/SMAD3 and VEGFR-1 signaling pathways play important roles in gastric cancer metastasis. SMAD3 phosphorylation is a crucial prognostic marker in gastric cancer.

AIM

To determine the prognostic value and relationship of SMAD3 phospho-isoforms and VEGFR-1 in gastric cancer.

METHODS

This was a single-center observational study which enrolled 98 gastric cancer patients and 82 adjacent normal gastric tissues from patients aged 32-84 years (median age 65) between July 2006 and April 2007. Patients were followed up until death or the study ended (median follow-up duration of 28.5 mo). The samples were used to generate tissue microarrays (TMAs) for immunohistochemical (IHC) staining. The expressions of TGF-β1, pSMAD3C(S423/425), pSMAD3L(S204), and VEGFR-1 in gastric cancer (GC) tumor tissue and normal tissue were measured by IHC staining using TMAs obtained from 98 GC patients. Prognosis and survival information of the patients was recorded by Outdo Biotech from May 2007 to July 2015. The relationship between TGF-β1, pSMAD3C(S423/425), pSMAD3L(S204), and VEGFR-1 protein expression levels was analyzed using Pearson's correlation coefficient. The relationship between protein expression levels and clinicopathological parameters was analyzed using the Chi-squared test. A survival curve was generated using the Kaplan-Meier survival analysis.

RESULTS

TGFβ-1 and VEGFR-1 expression was significantly upregulated in gastric cancer tissue compared to adjacent non-cancerous tissue. The positive expression of phosphorylated isoforms of Smad3 varied depending on the phosphorylation site [pSMAD3C(S423/425): 51.0% and pSMAD3L(S204): 31.6%]. High expression of pSMAD3L(S204) was significantly correlated with larger tumors (P = 0.038) and later N stages (P = 0.035). Additionally, high expression of VEGFR-1 was closely correlated with tumor size (P = 0.015) and pathological grading (P = 0.013). High expression of both pSMAD3L(S204) and VEGFR-1 was associated with unfavorable outcomes in terms of overall survival (OS). Multivariate analysis indicated that high expression of pSMAD3L(S204) and VEGFR-1 were independent risk factors for prognosis in GC patients. VEGFR-1 protein expression was correlated with TGF-β1 (r = 0.220, P = 0.029), pSMAD3C(S423/425) (r = 0.302, P = 0.002), and pSMAD3L(S204) (r = 0.201, P = 0.047), respectively. Simultaneous overexpression of pSMAD3L(S204) and VEGFR-1 was associated with poor OS in gastric cancer patients.

CONCLUSION

Co-upregulation of pSMAD3L(S204) and VEGFR-1 can serve as a predictive marker for poor gastric cancer prognosis, and pSMAD3L(204) may be involved in enhanced gastric cancer metastasis in a VEGFR-1-dependent manner.

Keywords: Gastric cancer, pSMAD3L(S204), pSMAD3C(S423/425), Survival, Transforming growth factor-β1, VEGFR-1

Core Tip: This study investigated the prognostic value and relationship between SMAD3 phospho-isoforms and VEGFR-1 in gastric cancer. The results showed that high expression of both pSMAD3L(S204) and VEGFR-1 was associated with poor overall survival in gastric cancer patients. Co-upregulation of pSMAD3L(S204) and VEGFR-1 can serve as a predictive marker for poor gastric cancer prognosis.