Abstract
Invasion and metastasis are the major causes of death in patients with esophageal squamous cell carcinoma (ESCC). Epithelial-mesenchymal transition (EMT) is a critical step in tumor progression and transforming growth factor-β1 (TGF-β1) signaling has been shown to play an important role in EMT. In this study, we investigated how TGF-β1 signaling pathways contributed to EMT in three ESCC cell lines as well as 100 patients of nomadic ethnic Kazakhs residing in northwest Xinjiang Province of China. In vitro analyses included Western blotting to detect the expression of TGF-β1/Smad and EMT-associated proteins in Eca109, EC9706 and KYSE150 cell lines following stimulation with recombinant TGF-β1 and SB431542, a potent inhibitor of ALK5 that also inhibits TGF-β type II receptor. TGF-β-activated Smad2/3 signaling in EMT was significantly upregulated as indicated by mesenchymal markers of N-cadherin and Vimentin, and in the meantime, epithelial marker, E-cadherin, was markedly downregulated. In contrast, SB431542 addition downregulated the expression of N-cadherin and Vimentin, but upregulated the expression of E-cadherin. Moreover, the TGF-β1-induced EMT promoted invasion capability of Eca109 cells. Tumor cells undergoing EMT acquire fibroblastoid-like phenotype. Expressed levels of TGF-β1/Smad signaling molecules and EMT-associated proteins were examined using immunohistochemical analyses in 100 ESCC tissues of Kazakh patients and 58 matched noncancerous adjacent tissues. The results showed that ESCC tissues exhibited upregulated expression of TGF-β1/Smad. We also analyzed the relationship between the above proteins and the patients' clinicopathological characteristics. The TGF-β1/Smad signaling pathway in human Eca109 ESCC cells may carry similar features as in Kazakh ESCC patients, suggesting that TGF-β1/Smad signaling pathway may be involved in the regulation of EMT in ethnic Kazakh patients with ESCC from Xinjiang, China.
Highlights
Esophageal cancer is the sixth most common cause of cancer-related death worldwide [1]
In Kazakh minorities residing in northwest Xinjiang, China, the incidence and mortality of esophageal squamous cell carcinoma (ESCC) are high with the latter being 69 per 100,000, much higher than the national average of ESCC mortality in China (15 per 100,000) and other ethnic groups residing in the same region (22.3 per 100,000) [2]
ESCC is often diagnosed at later stages when invasion and metastasis occur
Summary
Esophageal cancer is the sixth most common cause of cancer-related death worldwide [1]. The incidence and mortality rate of esophageal squamous cell carcinoma (ESCC) is high in nomadic Kazakh minority residing in northwest Xinjiang Province of China [2]. Deep invasion and metastasis remain the leading causes of death for ESCC patients. Epithelial-to-mesenchymal transition (EMT) plays an important role in cellular transdifferentiation during embryonic development, tumor invasion, and metastasis [3] and is one of the major molecular mechanisms through which invasion and metastasis are promoted during the oncogenic process. Besides the gain of mesenchymal markers, EMT provides cancer cells with the ability to migrate and invade into surrounding tissues, thereby promoting the subsequent formation of metastases [4]. The role of TGF-b1 in induced EMT in cancer progression has been intensively investigated, substantial evidence for the involvement of downstream signaling pathways of TGF-b1 in EMT, especially in the progression of esophageal squamous cell carcinoma, is lacking. The inhibitory Smad and Smad inhibit activation of the receptor-regulated Smads
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