Abstract

Invasion and metastasis of gastric cancer after curative resection remain the most common lethal outcomes. However, our current understanding of the molecular mechanism underlying gastric cancer metastasis is far from complete. Herein, we identified TOR signaling pathway regulator (TIPRL) as a novel metastasis suppressor in gastric cancer through genome-wide gene expression profiling analysis using mRNA microarray. Decreased TIPRL expression was detected in clinical gastric cancer specimens, and low TIPRL expression was correlated with more-advanced TNM stage, distant metastasis, and poor clinical outcome. Moreover, TIPRL was identified as a direct target of miR-216a-5p and miR-383-5p. Functional study revealed that re-expression of TIPRL in gastric cancer cell lines suppressed their migratory and invasive capacities, whereas inverse effects were observed in TIPRL-deficient models. Mechanistically, TIPRL downstream effectors and signaling pathways were investigated using mRNA microarray. Gene expression profiling revealed that TIPRL could not modulate the downstream genes at transcriptional levels, thereby implying that the regulation might occur at the post-transcriptional levels. We further demonstrated that TIPRL induced phosphorylation/activation of AMPK, which in turn attenuated phosphorylation of mTOR, p70S6K, and 4E-BP1, thereby leading to inactivation of mTOR signaling and subsequent suppression of cell migration/invasion in gastric cancer. Taken together, TIPRL acts as a novel metastasis suppressor in gastric cancer, at least in part, through regulating AMPK/mTOR signaling, likely representing a promising target for new therapies in gastric cancer.

Highlights

  • Gastric cancer is an aggressive disease and the third highest cause of cancer-related mortality, with nearly 1,000,000 new cases occurring worldwide each year [1]

  • To further explore the microarray data, we evaluated the transcriptional levels of TOR signaling pathway regulator (TIPRL), SERINC3, COPS6, and SELM in 40 frozen gastric tissues of gastric cancer patients by real-time PCR (Figures 1C–F)

  • Data mining of the prognostic effect of TIPRL mRNA expression from KaplanMeier plotter confirmed that lower TIPRL expression was associated with poor overall survival (OS), first progression survival (FP), and post-progression survival (PPS) in gastric cancer patients (Figure 1G, P = 1.1e-5, overall survival; Figure 1H, P = 8.5e-5, first progression survival; Figure 1I, P = 1.7e-5, post-progression survival)

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Summary

Introduction

Gastric cancer is an aggressive disease and the third highest cause of cancer-related mortality, with nearly 1,000,000 new cases occurring worldwide each year [1]. Gastric cancer is typically diagnosed as advanced disease [2]. The poor prognosis of patients with advanced gastric cancer is predominantly the result of the high rate of tumor metastasis and recurrence after curative resection [4, 5]. Gastric cancer metastasis is a complex and multistep process involving multiple factors and genes [6, 7]. Our current understanding of the molecular mechanism underlying gastric cancer metastasis is far from complete. Much hope is focused on increasing our understanding of the signaling pathways and underlying biology involved in gastric cancer metastasis in order to develop new therapeutic options. It is crucial to identify novel genes that govern gastric cancer metastasis and present predictive value for prognosis

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