Abstract
T-cell immunoglobulin and mucin domain-con-taining protein-3(TIM-3), a negative regulator of antitumor immune response, has been demonstrated to be involved in the onset and progression of several types of malignancies. The present study aimed to determine whether and how TIM‑3 plays such a role in esophageal squamous cell carcinoma(ESCC). TIM-3 expression was analyzed by immunohistochemistry and real‑time fluorescence quantitative PCR(qRT‑PCR) in ESCC and matched adjacent normal tissues. Functional experimentsinvitro were performed to elucidate the effect of TIM‑3 knockdown on the proliferation, apoptosis, migration, invasion and epithelial-mesenchymal transition(EMT) in Eca109 and TE‑1 cell lines. Our data revealed that TIM‑3 expression was significantly elevated at both the mRNA and protein levels in ESCC tissues compared with the levels in the matched adjacent normal tissues (both P<0.001). TIM‑3 expression was significantly associated with lymph node metastasis (P=0.008), tumor‑node‑metastasis(TNM) stage (P=0.042) and depth of tumor invasion (P=0.042). In addition, we observed a strong correlation between high TIM‑3 expression and a worse overall survival of ESCC patients (P=0.001). Functional study demonstrated that TIM‑3 knockdown markedly inhibited proliferation, migration and invasion of ESCC cell lines without affecting apoptosis. In addition, TIM‑3 depletion was associated with downregulation of matrix metalloproteinase(MMP)-9 and upregulation of tissue inhibitor of metalloproteinase(TIMP)-1, and with reversion of EMT, as reflected by higher levels of the epithelial marker E‑cadherin and lower levels of the mesenchymal markers N‑cadherin and vimentin. Further study found that TIM‑3 depletion suppressed the signaling pathway involving p‑Akt, p‑GSK‑3β and Snail. Taken together, these results suggest that TIM‑3 is a novel therapeutic target and prognostic biomarker for ESCC and promotes metastasis of ESCC by inducing EMT via, at least partially, the Akt/GSK-3β/Snail signaling pathway.
Highlights
Esophageal cancer is a common aggressive malignancy characterized by late diagnosis and early metastasis [1,2]
Further study found that taining protein‐3 (TIM‐3) depletion suppressed the signaling pathway involving p‐Akt, p‐GSK‐3β and Snail. These results suggest that TIM‐3 is a novel therapeutic target and prognostic biomarker for Esophageal squamous cell carcinoma (ESCC) and promotes metastasis of ESCC by inducing epithelial‐mesenchymal transition (EMT) via, at least partially, the Akt/GSK‐3β/Snail signaling pathway
TIM‐3 mRNA levels were analyzed by quantitative real‐time reverse transcriptase‐PCR (qRT‐PCR) in 40 pairs of ESCC and matched adjacent normal tissues
Summary
Esophageal cancer is a common aggressive malignancy characterized by late diagnosis and early metastasis [1,2]. Esophageal cancer is the eighth most common cancer and sixth most common cause of cancer‐related deaths worldwide, with an estimated 455,800 new cases and 400,200 deaths occurring in 2012 alone [3,4]. In 2015, an estimated 16,980 individuals were diagnosed with esophageal cancer in the USA, and 15,590 individuals succumbed to the disease, making it the ninth leading cause of cancer‐related deaths in that country [5]. Esophageal cancers are histologically classified as squamous cell carcinoma (SCC) or adenocarcinoma [3]. Esophageal squamous cell carcinoma (ESCC) represents a predominant type of esophageal cancer, accounting for approximately 90% of all esophageal cancers [6]. Effective treatments against ESCC are needed, such as treatments targeting molecules and pathways activated in this disease
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