Elevated Expression of Calpain-4 Predicts Poor Prognosis in Patients with Gastric Cancer after Gastrectomy.

Peike Peng,Jianxin Gu,Xuefei Wang,Lili Li,Jing Qin,Jie Zhang,Shushu Song,Can Li,Lingqiang Min,Mingming Zhang,Caiting Yang,Junjie Zhao,Hao Wu,Yuanyuan Ruan,Hongshan Wang,Miaomiao Shao

doi:10.3390/ijms17101612

Abstract

Calpain-4 belongs to the calpain family of calcium-dependent cysteine proteases, and functions as a small regulatory subunit of the calpains. Recent evidence indicates that calpain-4 plays critical roles in tumor migration and invasion. However, the roles of calpain-4 in gastric tumorigenesis remain poorly understood. Herein, we examined calpain-4 expression by immunohistochemical staining on tissue microarrays containing tumor samples of 174 gastric cancer patients between 2004 and 2008 at a single center. The Kaplan-Meier method was used to compare survival curves, and expression levels were correlated to clinicopathological factors and overall survival. Our data demonstrated that calpain-4 was generally increased in gastric cancer cell lines and primary tumor tissues. High expression of calpain-4 was positively associated with vessel invasion, lymph node metastasis, and advanced TNM (Tumor Node Metastasis) stage. Multivariate analysis identified calpain-4 as an independent prognostic factor for poor prognosis. A predictive nomogram integrating calpain-4 expression with other independent prognosticators was constructed, which generated a better prognostic value for overall survival of gastric cancer patients than a TNM staging system. In conclusion, calpain-4 could be regarded as a potential prognosis indicator for clinical outcomes in gastric cancer.

Highlights

Gastric cancer remains the fifth most common malignancy and the third leading cause of cancer-associated death worldwide, especially in Asia [1]
To understand whether calpain-4 was involved in gastric carcinogenesis, we first examined the protein expression of calpain-4 in gastric cancer tissues compared with matched adjacent normal gastric mucosa by Western blot (Figure 1A)
We investigated the mRNA levels of calpain-4 in 33 paired gastric cancer samples, and the results showed that the mRNA expression of calpain-4 was higher in tumors (Figure 1B)

Summary

Introduction

Gastric cancer remains the fifth most common malignancy and the third leading cause of cancer-associated death worldwide, especially in Asia [1]. Due to the lack of specific symptoms at the early stage, over 80% of patients with gastric cancer are diagnosed at an advanced and unsuitable stage for surgical resection, which is the major reason for a poor prognosis [2]. The clinically used prognostic model for outcomes of gastric cancer patients mainly relies on a tumor cell-derived TNM (Tumor Node Metastasis) stage [3]. Useful prognostic biomarkers or underlying mechanisms are urgently needed to refine risk stratification for prognosis of patients with gastric cancer. The archetypal members of calpain family, calpain-1 (μ-form) and calpain-2 (m-form), are ubiquitously expressed, while the other members are tissue-specific cysteine proteases that proteolyze different kinds of substrates, leading to their degradation or functional modulation [6]. The roles of calpain-4 in gastric carcinoma remain poorly understood

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Results