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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

Kaplan–Meier survival curves for patients with overexpressed SLC39A6 and those with low SLC39A6 levels. a ESCC patients with overexpressed SLC39A6 (IS ≥ 5) experienced a significantly shorter survival period after surgery than those with low SLC39A6 levels (IS < 5) (p < 0.01). b Patients with SLC39A6 overexpression had a greater risk of death than those with lower SLC39A6 levels (p < 0.01). c, d Patients with high SLC39A6 expression shows the worse overall survival at stage I + II than those with low-expression (p < 0.05)
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Fig4: Kaplan–Meier survival curves for patients with overexpressed SLC39A6 and those with low SLC39A6 levels. a ESCC patients with overexpressed SLC39A6 (IS ≥ 5) experienced a significantly shorter survival period after surgery than those with low SLC39A6 levels (IS < 5) (p < 0.01). b Patients with SLC39A6 overexpression had a greater risk of death than those with lower SLC39A6 levels (p < 0.01). c, d Patients with high SLC39A6 expression shows the worse overall survival at stage I + II than those with low-expression (p < 0.05)

Mentions: The association between SLC39A6 protein expression and overall survival (OS) of ESCC was estimated using log-rank test and multivariable Cox proportional hazard regression analysis. Of the 142 ESCC patients examined from the Han ethnic, clinical follow-up information was available for 75 patients. The median survival time of patients with lower SLC39A6 expression was 38.21 months (range 1–96 months), whereas that of patients with SLC39A6 overexpression was only 12.18 months (range 1–78 months). As shown in Fig. 4a, Kaplan–Meier survival analysis showed that ESCC patients with higher expression of SLC39A6 protein had significantly worse prognosis than ESCC patients with low or no expression (log-rank test, χ2 = 6.749, P = 0.009). Patients with SLC39A6 overexpression had worse OS and greater risk of death after surgery than those with a weak or negative SLC39A6 expression (P = 0.009, Fig. 4b). Furthermore, when the ESCC patients were stratified according to clinical stage, the survival rates of patients with SLC39A6 overexpression cancer were significantly lower than those of patients with SLC39A6 down-expression in early stage ESCC (P = 0.036, Fig. 4c). By contrast, SLC39A6 was not related to ESCC survival in later stage ESCC (P = 0.273, Fig. 4d).Fig. 4


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)

Kaplan–Meier survival curves for patients with overexpressed SLC39A6 and those with low SLC39A6 levels. a ESCC patients with overexpressed SLC39A6 (IS ≥ 5) experienced a significantly shorter survival period after surgery than those with low SLC39A6 levels (IS < 5) (p < 0.01). b Patients with SLC39A6 overexpression had a greater risk of death than those with lower SLC39A6 levels (p < 0.01). c, d Patients with high SLC39A6 expression shows the worse overall survival at stage I + II than those with low-expression (p < 0.05)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: Kaplan–Meier survival curves for patients with overexpressed SLC39A6 and those with low SLC39A6 levels. a ESCC patients with overexpressed SLC39A6 (IS ≥ 5) experienced a significantly shorter survival period after surgery than those with low SLC39A6 levels (IS < 5) (p < 0.01). b Patients with SLC39A6 overexpression had a greater risk of death than those with lower SLC39A6 levels (p < 0.01). c, d Patients with high SLC39A6 expression shows the worse overall survival at stage I + II than those with low-expression (p < 0.05)
Mentions: The association between SLC39A6 protein expression and overall survival (OS) of ESCC was estimated using log-rank test and multivariable Cox proportional hazard regression analysis. Of the 142 ESCC patients examined from the Han ethnic, clinical follow-up information was available for 75 patients. The median survival time of patients with lower SLC39A6 expression was 38.21 months (range 1–96 months), whereas that of patients with SLC39A6 overexpression was only 12.18 months (range 1–78 months). As shown in Fig. 4a, Kaplan–Meier survival analysis showed that ESCC patients with higher expression of SLC39A6 protein had significantly worse prognosis than ESCC patients with low or no expression (log-rank test, χ2 = 6.749, P = 0.009). Patients with SLC39A6 overexpression had worse OS and greater risk of death after surgery than those with a weak or negative SLC39A6 expression (P = 0.009, Fig. 4b). Furthermore, when the ESCC patients were stratified according to clinical stage, the survival rates of patients with SLC39A6 overexpression cancer were significantly lower than those of patients with SLC39A6 down-expression in early stage ESCC (P = 0.036, Fig. 4c). By contrast, SLC39A6 was not related to ESCC survival in later stage ESCC (P = 0.273, Fig. 4d).Fig. 4

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