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

Cui XB, Shen YY, Jin TT, Li S, Li TT, Zhang SM, Peng H, Liu CX, Li SG, Yang L, Li N, Hu JM, Jiang JF, Li M, Liang WH, Li Y, Wei YT, Sun ZZ, Wu CY, Chen YZ, Li F - J Transl Med (2015)

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, North 4th Road, 832002, Shihezi, China. cuixiaobin4363@foxmail.com.

ABSTRACT

Background: Esophageal 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.

Methods: Multiethnic 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.

Results: SLC39A6 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.

Conclusions: Combined, 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.

No MeSH data available.


Related in: MedlinePlus

Representative immunohistochemical staining of SLC39A6 in Kazakh ethnic. The negative controls for the normal tissues (a) and esophageal cancer (b) specimens (magnification ×100). Representative SLC39A6 immunostaining in non-tumor esophageal (c) and esophagus squamous cell carcinoma (d) tissues with weak, moderate, or strong expression (top panel magnification ×40; middle panel magnification ×100; bottom panels magnification ×200). eBoxplot shows that SLC39A6 expression levels in ESCC are significantly higher than that in normal esophageal squamous epithelium from Kazakh population (p < 0.001). f Expression levels of SLC39A6 proteins were determined in esophageal carcinoma cell lines (Eca109, EC9706, TE-1, and KYSE-150) and a normal esophageal epithelium cell line (HEEC) using western blotting
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Fig2: Representative immunohistochemical staining of SLC39A6 in Kazakh ethnic. The negative controls for the normal tissues (a) and esophageal cancer (b) specimens (magnification ×100). Representative SLC39A6 immunostaining in non-tumor esophageal (c) and esophagus squamous cell carcinoma (d) tissues with weak, moderate, or strong expression (top panel magnification ×40; middle panel magnification ×100; bottom panels magnification ×200). eBoxplot shows that SLC39A6 expression levels in ESCC are significantly higher than that in normal esophageal squamous epithelium from Kazakh population (p < 0.001). f Expression levels of SLC39A6 proteins were determined in esophageal carcinoma cell lines (Eca109, EC9706, TE-1, and KYSE-150) and a normal esophageal epithelium cell line (HEEC) using western blotting

Mentions: SLC39A6 protein expression was then externally validated in the cohort of patients from the Kazakh ethnic group (Table 3). As shown in Fig. 2, the negative controls for the normal tissues (Fig. 2a) and esophageal cancer (Fig. 2b) specimens were negative. Consistent with the results of IHC analysis of SLC39A6 protein alteration in Han ethnic, SLC39A6 expression was upregulated in 68/86 (79.07 %) of ESCC specimens, and only in 14/41 (34.15 %) in normal samples (Fig. 2c, d). The expression levels of SLC39A6 protein in ESCC tissues were significantly higher than those in the corresponding normal tissues in the Kazakh population (P < 0.001, Fig. 2e). These findings are in accordance with the results from the Han population. The results indicate no difference in terms of the staining pattern and frequency of SLC39A6 protein expression between different racial tissues types collected from the Chinese Han and Kazakh populations, as well as those residing in western China.Table 3


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

Cui XB, Shen YY, Jin TT, Li S, Li TT, Zhang SM, Peng H, Liu CX, Li SG, Yang L, Li N, Hu JM, Jiang JF, Li M, Liang WH, Li Y, Wei YT, Sun ZZ, Wu CY, Chen YZ, Li F - J Transl Med (2015)

Representative immunohistochemical staining of SLC39A6 in Kazakh ethnic. The negative controls for the normal tissues (a) and esophageal cancer (b) specimens (magnification ×100). Representative SLC39A6 immunostaining in non-tumor esophageal (c) and esophagus squamous cell carcinoma (d) tissues with weak, moderate, or strong expression (top panel magnification ×40; middle panel magnification ×100; bottom panels magnification ×200). eBoxplot shows that SLC39A6 expression levels in ESCC are significantly higher than that in normal esophageal squamous epithelium from Kazakh population (p < 0.001). f Expression levels of SLC39A6 proteins were determined in esophageal carcinoma cell lines (Eca109, EC9706, TE-1, and KYSE-150) and a normal esophageal epithelium cell line (HEEC) using western blotting
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4595240&req=5

Fig2: Representative immunohistochemical staining of SLC39A6 in Kazakh ethnic. The negative controls for the normal tissues (a) and esophageal cancer (b) specimens (magnification ×100). Representative SLC39A6 immunostaining in non-tumor esophageal (c) and esophagus squamous cell carcinoma (d) tissues with weak, moderate, or strong expression (top panel magnification ×40; middle panel magnification ×100; bottom panels magnification ×200). eBoxplot shows that SLC39A6 expression levels in ESCC are significantly higher than that in normal esophageal squamous epithelium from Kazakh population (p < 0.001). f Expression levels of SLC39A6 proteins were determined in esophageal carcinoma cell lines (Eca109, EC9706, TE-1, and KYSE-150) and a normal esophageal epithelium cell line (HEEC) using western blotting
Mentions: SLC39A6 protein expression was then externally validated in the cohort of patients from the Kazakh ethnic group (Table 3). As shown in Fig. 2, the negative controls for the normal tissues (Fig. 2a) and esophageal cancer (Fig. 2b) specimens were negative. Consistent with the results of IHC analysis of SLC39A6 protein alteration in Han ethnic, SLC39A6 expression was upregulated in 68/86 (79.07 %) of ESCC specimens, and only in 14/41 (34.15 %) in normal samples (Fig. 2c, d). The expression levels of SLC39A6 protein in ESCC tissues were significantly higher than those in the corresponding normal tissues in the Kazakh population (P < 0.001, Fig. 2e). These findings are in accordance with the results from the Han population. The results indicate no difference in terms of the staining pattern and frequency of SLC39A6 protein expression between different racial tissues types collected from the Chinese Han and Kazakh populations, as well as those residing in western China.Table 3

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Key Laboratory for Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, North 4th Road, 832002, Shihezi, China. cuixiaobin4363@foxmail.com.

ABSTRACT

Background: Esophageal 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.

Methods: Multiethnic 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.

Results: SLC39A6 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.

Conclusions: Combined, 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.

No MeSH data available.


Related in: MedlinePlus