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

doi:10.4251/wjgo.v16.i1.118

Prognostic significance and relationship of SMAD3 phospho-isoforms and VEGFR-1 in gastric cancer: A clinicopathological study

World J Gastrointest Oncol. 2024 Jan 15;16(1):118-132. doi: 10.4251/wjgo.v16.i1.118.

Authors

Shi-Lin Lv¹, Pei Guo², Jun-Rong Zou³, Ren-Sheng Chen⁴, Ling-Yu Luo¹, De-Qiang Huang⁵

Affiliations

¹ Hospital of Gastroenterology, Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China.
² Department of Pathology, Shenzhen Hospital of Southern Medical University, Shenzhen 518000, Guangdong Province, China.
³ Institute of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, Jiangxi Province, China.
⁴ Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China.
⁵ Hospital of Gastroenterology, Institute of Digestive Diseases, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China. hdq0515@ncu.edu.cn.

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; Survival; Transforming growth factor-β1; VEGFR-1; pSMAD3C(S423/425); pSMAD3L(S204).