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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

Receiver operating characteristic curve analysis for SLC39A6 immunohistochemical scores for detecting precancerous lesions and ESCC tissues. a Kazakh ethnic ESCC tissues. b Han ESCC tissues. c HGIN tissues. d LGIN tissues. The AUC in Kazakh ESCC, Han ethnic ESCC, HGIN, and LGIN is 0.853, 0.78, 0.822, and 0.743, respectively
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Fig3: Receiver operating characteristic curve analysis for SLC39A6 immunohistochemical scores for detecting precancerous lesions and ESCC tissues. a Kazakh ethnic ESCC tissues. b Han ESCC tissues. c HGIN tissues. d LGIN tissues. The AUC in Kazakh ESCC, Han ethnic ESCC, HGIN, and LGIN is 0.853, 0.78, 0.822, and 0.743, respectively

Mentions: Using the distant normal mucosa as the control, the receiver operating characteristic (ROC) curves for various types of tissues clearly illustrate the point on the curve closest to (0.0, 1.0), which maximizes both sensitivity and specificity for ESCC, HGIN, and LGIN. The score with the most areas under the ROC curve (AUC) and having both maximum “sensitivity” and “1-specificity” was selected as the cut-off score. We found that the immunohistochemical cut-off scores of SLC39A6 easily distinguished the ESCC, HGIN, and LGIN tissues from the normal esophageal tissues, all of which demonstrated high sensitivity and specificity values according to the area under ROC curve (all >0.7, Fig. 3; Additional file 4: Table S3). These results support the notion that SLC39A6 may be a potential diagnostic biomarker for ESCC and ESIN.Fig. 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)

Receiver operating characteristic curve analysis for SLC39A6 immunohistochemical scores for detecting precancerous lesions and ESCC tissues. a Kazakh ethnic ESCC tissues. b Han ESCC tissues. c HGIN tissues. d LGIN tissues. The AUC in Kazakh ESCC, Han ethnic ESCC, HGIN, and LGIN is 0.853, 0.78, 0.822, and 0.743, respectively
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Receiver operating characteristic curve analysis for SLC39A6 immunohistochemical scores for detecting precancerous lesions and ESCC tissues. a Kazakh ethnic ESCC tissues. b Han ESCC tissues. c HGIN tissues. d LGIN tissues. The AUC in Kazakh ESCC, Han ethnic ESCC, HGIN, and LGIN is 0.853, 0.78, 0.822, and 0.743, respectively
Mentions: Using the distant normal mucosa as the control, the receiver operating characteristic (ROC) curves for various types of tissues clearly illustrate the point on the curve closest to (0.0, 1.0), which maximizes both sensitivity and specificity for ESCC, HGIN, and LGIN. The score with the most areas under the ROC curve (AUC) and having both maximum “sensitivity” and “1-specificity” was selected as the cut-off score. We found that the immunohistochemical cut-off scores of SLC39A6 easily distinguished the ESCC, HGIN, and LGIN tissues from the normal esophageal tissues, all of which demonstrated high sensitivity and specificity values according to the area under ROC curve (all >0.7, Fig. 3; Additional file 4: Table S3). These results support the notion that SLC39A6 may be a potential diagnostic biomarker for ESCC and ESIN.Fig. 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