Vesicle-mediated transport-related gene SEC23A promotes cell proliferation by regulating cell cycle leading to gastric cancer progression

Abstract

Gastric cancer (GC) is a highly prevalent and lethal gastrointestinal cancer. Dysregulation of vesicle-mediated transport-related genes (VMTRGs) is closely associated with tumorigenesis and disease progression. However, the prognostic value of VMTRGs in GC remains unclear. In this study, on the basis of our proteomics data and public databases, we identify differentially expressed VMTRGs in infiltrative-type GC with more metastases and recurrences identified by Ming’s classification. Least absolute shrinkage and selection operator (LASSO) regression identifies 3 VMTRGs (SEC23A, RAB31, and GABARAPL2) from 41 infiltrative-associated VMTRGs, based on which a risk model Vesicle-Infiltrative Lasso System (VILS) is constructed, and its effectiveness and potential importance are validated by immune microenvironment analysis and functional enrichment analysis. As an independent prognostic factor for GC, VILS, combined with other clinically independent prognostic factors to form a nomogram, is effective in predicting GC prognosis. The VILS high-risk group has higher M2 macrophage and cancer-associated fibroblast infiltration, and lower infiltration of Th1 cells and natural killer cells. SEC23A is highly expressed in GC tissues and cells. The importance of SEC23A in GC cells is evaluated by in vitro assays including colony formation assay and CCK-8 assay, and by in vivo assay using a subcutaneous xenograft mouse model. The results show that SEC23A promotes GC cell proliferation and tumor growth through regulation of the cell cycle in vitro and in vivo. VILS provides excellent prognostic prediction for GC patients and is correlated with antitumor immune cell infiltration. SEC23A, the dominant gene of VILS, is highly expressed in GC and promotes GC growth and malignant progression through various molecular mechanisms. Our study reveals the effect of SEC23A on the proliferation of gastric cancer cells for the first time. Therefore, SEC23A has the potential to be a new therapeutic target for the diagnosis and treatment of GC.

1. Introduction

Gastric cancer (GC) is a highly prevalent and lethal gastrointestinal cancer worldwide [1]. According to its histological variants and biological behavior, GC can be broadly divided into two categories: expanding and infiltrative types by Ming’s classification [2,3]. Studies have shown that infiltrative type GC has a worse prognosis than expanding type GC [4]. The expending type eventually forms discrete tumor nodules, whereas the infiltrative type tumor cells lead to diffuse involvement of the stomach [5]. However, the specific mechanism that leads to the difference in biological behavior and prognosis between these two types of GC has not been fully clarified.

Once biosynthesis is complete, each protein must be transported to the appropriate cellular compartment or secreted extracellularly to function. Vesicular transport plays a pivotal role in the transfer of protein molecules and the secretory activities of cells [6]. The set of genes that mediate these functions is known as vesicle-mediated transport-related genes (VMTRGs). The proteins encoded by genes contained within VMTRGs include Ras-related proteins in the brain (Rab) family, the transmembrane emp24 domain (TMED) family, coat protein complex (COP) I, the kinesin superfamily, and COP II proteins [7]. COP I and COP II were first identified as complexes involved in vesicular trafficking between the endoplasmic reticulum (ER) and Golgi complex [8]. The aberrant expressions of VMTRGs have been implicated in human disease and tumors [9–11].

COPII has been reported to mediate the first step of the protein secretion pathway and to play a part in tumors. SEC23A is a core member of COP II [12], and in several tumors, including breast cancer [13], bladder cancer [14], melanoma [15], GC [16], the expression of SEC23A is upregulated. SEC23A was identified as an independent prognostic factor correlated with the MAPK pathway in bladder cancer [14], and it may act as a suppressor of oligometastatic to polymetastatic progression in melanoma [17]. SEC23A is significantly overexpressed in GC. Some studies seem to indicate that SEC23A plays an inhibitory role in malignant development and tumor metastasis [15, 17–19], but one study showed that elevated expression of SEC23A is associated with adverse GC prognosis [16]. Another study showed that SEC23A affects the autophagy of cancer cells [20]. However, the exact role of SEC23A in GC and the exact mechanism are yet unclear.