Abstract
Background Thioredoxin-1 (Trx-1) is a small redox protein, which plays an important role in many biological processes. Although increased expression of Trx-1 in various solid tumors has been reported, the prognostic significance and function of Trx-1 in human gastric cancer (GC) are still unclear. Here, we investigated the clinical and prognostic significance of Trx-1 expression and the function and mechanism of Trx-1 in human GC. Methods We analyzed Trx-1 mRNA expression from the GEO database and Trx-1 protein expression in 144 GC tissues using immunohistochemistry. Effects of Trx-1 on GC cell were assessed in vitro and in vivo through Trx-1 knockdown or overexpression. The antitumor effects of the Trx-1 inhibitor, PX-12, on GC cells were investigated. PTEN and p-AKT expressions were evaluated by Western blotting. Results Increased Trx-1 expression was found in GC tissues and associated with poor prognosis and aggressive clinicopathological characteristics in patients with GC. High Trx-1 expression predicted poor prognosis, and its expression was an independent prognostic factor for overall survival of GC patients. Knockdown of Trx-1 expression inhibited GC cell growth, migration, and invasion in vitro and tumor growth and lung metastasis in vivo. Conversely, overexpression of Trx-1 promoted GC cell growth, migration, and invasion. We also found that PX-12 inhibited GC cell growth, migration, and invasion. Overexpression of Trx-1 caused a decrease in PTEN and increase in p-AKT levels whereas silencing Trx-1 caused an increase in PTEN and decrease in p-AKT levels in GC cells. Inhibition of AKT signaling pathway by MK2206 also inhibited GC cell growth, migration, and invasion. Conclusion Our results indicate that Trx-1 may be a promising prognostic indicator and therapeutic target for GC patients.
Highlights
Gastric cancer (GC) is the fourth most diagnosed cancer and the second leading cause of cancer-related death worldwide [1]. 70% of gastric cancer (GC) deaths occur in developing countries with China accounting for approximately 40% of them [2]
We analyzed the association between Trx-1 mRNA expression and patient survival using GSE15460 obtained from the Gene Expression Omnibus (GEO) database and found that patients with high Trx-1 expression levels had shorter postoperative survival time than patients with low Trx-1 expression levels (P = 0 0176, Figure 1(b))
Kaplan-Meier analysis showed that lower Trx-1 protein expression was linked to markedly longer overall survival of GC patients (P < 0 001, Figure 1(e))
Summary
Gastric cancer (GC) is the fourth most diagnosed cancer and the second leading cause of cancer-related death worldwide [1]. 70% of GC deaths occur in developing countries with China accounting for approximately 40% of them [2]. Its overexpression is associated with cancer cell proliferation, inhibition of apoptosis, tumor aggressiveness, and poor prognosis in patients [18, 19]. Increased expression of Trx-1 in various solid tumors has been reported, the prognostic significance and function of Trx-1 in human gastric cancer (GC) are still unclear. Increased Trx-1 expression was found in GC tissues and associated with poor prognosis and aggressive clinicopathological characteristics in patients with GC. High Trx-1 expression predicted poor prognosis, and its expression was an independent prognostic factor for overall survival of GC patients. Knockdown of Trx-1 expression inhibited GC cell growth, migration, and invasion in vitro and tumor growth and lung metastasis in vivo. Overexpression of Trx-1 promoted GC cell growth, migration, and invasion. Our results indicate that Trx-1 may be a promising prognostic indicator and therapeutic target for GC patients
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