SLC39A6: a potential target for diagnosis and therapy of esophageal carcinoma

Abstract

BackgroundEsophageal squamous cell carcinoma (ESCC) is a highly lethal cancer, and its underlying molecular mechanisms are poorly understood. Recent large-scale genome-wide association studies in Chinese Han populations have identified an ESCC susceptibility locus within the SLC39A6 gene. Here, we sought to explore the expression and biological function of SLC39A6 in ESCC.MethodsMultiethnic validation of SLC39A6 protein expression was performed in different cohorts of patients from Chinese Han and Kazakh populations in the Xinjiang region by immunohistochemistry. The associations among SLC39A6 expression, clinicopathological parameters, and prognosis outcomes of ESCC were analyzed. And the effects of SLC39A6 silencing by siRNA on cell proliferation, apoptosis, and invasiveness, as well as the proteins involved in epithelial-to-mesenchymal transition (EMT) of esophageal cancer cells, were studied.ResultsSLC39A6 protein expression increased progressively from normal esophageal epithelium (NEE) to low-grade intraepithelial neoplasia to ESCC, and finally reached the highest in high-grade intraepithelial neoplasia from Han ethnic. Similarly, SLC39A6 protein was significantly overexpressed in Kazakh ethnic ESCC compared with that in NEE. Increased expression of SLC39A6 was found to be closely correlated with histological grade and early Tumor-Node-Metastasis stage I/II. High tumorous SLC39A6 expression was significantly correlated with shorter overall survival (OS). Cox regression analysis confirmed that SLC39A6 expression was an independent prognostic factor for poor OS in ESCC. Experimentally, the suppression of SLC39A6 expression promoted ESCC cell apoptosis but abrogated proliferation and invasion, and induced an EMT phenotype that included enhanced expression of E-cadherin, loss of vimentin, and morphological changes in ESCC cells in vitro.ConclusionsCombined, our findings highlight a tumor-promoting role for SLC39A6 in ESCC, suggesting that SLC39A6 could serve as an early detector of high-risk subjects and prognostic biomarker. The targeting of SLC39A6 might be a potential therapeutic strategy for blocking ESCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0681-z) contains supplementary material, which is available to authorized users.

Tissue protein biomarker candidates to predict progression of esophageal squamous cell carcinoma and precancerous lesions

“…CTGF protein expression was notably correlated to poor survival of ESCC patients after 12 years of follow‐up . An atypical expression pattern of SLC39A6 and PFN2 was observed between different lesion stages, showing that high expression of SLC39A6 and PFN2 was associated with shorter overall survival . Low expression of certain proteins has also been associated with poor prognosis.…”

“…These studies suggest that deregulated proteins with no obvious linear patterns (i.e., not trending up or down) could be potential biomarkers, and that focusing on distinct precancerous lesions rather than invasive carcinoma may help uncover new potential protein biomarkers for early detection. Another study reported an atypical expression pattern of SLC39A6 and profilin 2 (PFN2) at different stages; SLC39A6 and PFN2 expression increased in succession from normal to LGIN, to ESCC, and, finally, reached their peak in HGIN lesions, suggesting the potential diagnostic role of SLC39A6 and PFN2 in ESCC …”

“…Another study reported an atypical expression pattern of SLC39A6 and profilin 2 (PFN2) at different stages; SLC39A6 and PFN2 expression increased in succession from normal to LGIN, to ESCC, and, finally, reached their peak in HGIN lesions, suggesting the potential diagnostic role of SLC39A6 and PFN2 in ESCC. 38,39 Expression pattern and position of biomarker. Other studies have focused not only on the expression level, but on the expression pattern and position of protein biomarker candidates ( Table 2).…”

“…32 An atypical expression pattern of SLC39A6 and PFN2 was observed between different lesion stages, showing that high expression of SLC39A6 and PFN2 was associated with shorter overall survival. 38,39 Low expression of certain proteins has also been associated with poor prognosis. For instance, low TUSC3 expression has been statistically significantly associated with shorter overall survival.…”

Tobacco: Incessant Human Health Menace (A Review)

“…SLC39A6 protein a member of a new subfamily of zinc transporters, is involved in maintaining the intracellular homeostasis of zinc, an ion that is essential in the control of gene transcription, differentiation, development and growth, suggesting that its altered distribution might promote tumorigenesis and targeting SLC39A6 might be a potential therapeutic strategy [24]. The Transient Receptor Potential (TRP) channels family which consists of seven different subfamilies, namely TRPC (Canonical), TRPV (Vanilloid), TRPM (Melastatin), TRPML (Mucolipin), TRPP (Polycystin), and TRPA (Ankyrin transmembrane protein) and TRPN (NomPC-like), are related to several physiological and pathological processes.…”