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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

Immunohistochemical analysis of SLC39A6 in non-tumor esophageal, precancerous lesions, and ESCC tissues from Chinese Han ethnic. Representative SLC39A6 immunostaining in a non-tumor esophageal (top panel magnification ×40; middle panel magnification ×100; bottom panels magnification ×200), precancerous lesions. b LGIN and HGIN (top panel magnification ×40; middle panel magnification ×100; bottom panels magnification ×200), and c ESCC tissues (top panel magnification ×40; middle panel magnification ×100; bottom panels magnification ×200). d SLC39A6 immunoreactivity was scored in human normal esophageal squamous epithelium, precancerous lesions, and ESCC tissues. (*p < 0.05; **p < 0.01; ***p < 0.001). e The four level score (0–1, 2–4, 5–8, and 9–12) distribution of SLC39A6 protein expression in normal, precancerous lesions, and ESCC
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Fig1: Immunohistochemical analysis of SLC39A6 in non-tumor esophageal, precancerous lesions, and ESCC tissues from Chinese Han ethnic. Representative SLC39A6 immunostaining in a non-tumor esophageal (top panel magnification ×40; middle panel magnification ×100; bottom panels magnification ×200), precancerous lesions. b LGIN and HGIN (top panel magnification ×40; middle panel magnification ×100; bottom panels magnification ×200), and c ESCC tissues (top panel magnification ×40; middle panel magnification ×100; bottom panels magnification ×200). d SLC39A6 immunoreactivity was scored in human normal esophageal squamous epithelium, precancerous lesions, and ESCC tissues. (*p < 0.05; **p < 0.01; ***p < 0.001). e The four level score (0–1, 2–4, 5–8, and 9–12) distribution of SLC39A6 protein expression in normal, precancerous lesions, and ESCC

Mentions: During the multi-stage development of ESCC in the Chinese Han population, IHC analysis showed that the frequency of SLC39A6 protein overexpression was lowest in normal samples (14.39 %) and increased gradually during the evolution of esophageal carcinogenesis, with 51.85 % (42/81) of LGIN and 76.47 % (39/52) of HGIN, and a slight decrease at 66.90 % (95/142) of ESCC but still showing high SLC39A6 protein expression. In NEE, SLC39A6 labeling was weak and predominantly expressed in the cytoplasm of basal cells and suprabasal layer cells (Fig. 1a); however, SLC39A6 was highly expressed in HGIN and ESCC cells with the signal strongest in nuclei/cytoplasm (Fig. 1b, c). Boxplot showed that the trend of SLC39A6 immunoreactivity score increased in a stepwise manner from normal, LGIN, and ESCC, and peaked in HGIN using the t tests (Fig. 1d). In addition, the four level score (0–1, 2–4, 5–8, and 9–12) distribution of SLC39A6 protein expression in normal, precancerous lesions, and ESCC was significantly distinct (Fig. 1e). Furthermore, as shown in Table 2, in-depth analysis using the Chi square test revealed that the overexpression rates of SLC39A6 protein increased significantly in LGIN, HGIN, and ESCC compared with normal tissues (P < 0.001). Significant differences were also observed between LGIN and HGIN (P = 0.004), as well as between LGIN and ESCC (P = 0.037), whereas no significant differences were found between LGIN and ESCC (P > 0.05, Table 2). However, using the McNemar test, we did not found the SLC39A6 expression significantly differs between ESCC and their corresponding HGIN tissues (P = 0.076); similarly, the SLC39A6 expression also does not significantly differ between ESCC and their corresponding LGIN tissues (P = 0.229; Additional file 3: Table S2).Fig. 1


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)

Immunohistochemical analysis of SLC39A6 in non-tumor esophageal, precancerous lesions, and ESCC tissues from Chinese Han ethnic. Representative SLC39A6 immunostaining in a non-tumor esophageal (top panel magnification ×40; middle panel magnification ×100; bottom panels magnification ×200), precancerous lesions. b LGIN and HGIN (top panel magnification ×40; middle panel magnification ×100; bottom panels magnification ×200), and c ESCC tissues (top panel magnification ×40; middle panel magnification ×100; bottom panels magnification ×200). d SLC39A6 immunoreactivity was scored in human normal esophageal squamous epithelium, precancerous lesions, and ESCC tissues. (*p < 0.05; **p < 0.01; ***p < 0.001). e The four level score (0–1, 2–4, 5–8, and 9–12) distribution of SLC39A6 protein expression in normal, precancerous lesions, and ESCC
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4595240&req=5

Fig1: Immunohistochemical analysis of SLC39A6 in non-tumor esophageal, precancerous lesions, and ESCC tissues from Chinese Han ethnic. Representative SLC39A6 immunostaining in a non-tumor esophageal (top panel magnification ×40; middle panel magnification ×100; bottom panels magnification ×200), precancerous lesions. b LGIN and HGIN (top panel magnification ×40; middle panel magnification ×100; bottom panels magnification ×200), and c ESCC tissues (top panel magnification ×40; middle panel magnification ×100; bottom panels magnification ×200). d SLC39A6 immunoreactivity was scored in human normal esophageal squamous epithelium, precancerous lesions, and ESCC tissues. (*p < 0.05; **p < 0.01; ***p < 0.001). e The four level score (0–1, 2–4, 5–8, and 9–12) distribution of SLC39A6 protein expression in normal, precancerous lesions, and ESCC
Mentions: During the multi-stage development of ESCC in the Chinese Han population, IHC analysis showed that the frequency of SLC39A6 protein overexpression was lowest in normal samples (14.39 %) and increased gradually during the evolution of esophageal carcinogenesis, with 51.85 % (42/81) of LGIN and 76.47 % (39/52) of HGIN, and a slight decrease at 66.90 % (95/142) of ESCC but still showing high SLC39A6 protein expression. In NEE, SLC39A6 labeling was weak and predominantly expressed in the cytoplasm of basal cells and suprabasal layer cells (Fig. 1a); however, SLC39A6 was highly expressed in HGIN and ESCC cells with the signal strongest in nuclei/cytoplasm (Fig. 1b, c). Boxplot showed that the trend of SLC39A6 immunoreactivity score increased in a stepwise manner from normal, LGIN, and ESCC, and peaked in HGIN using the t tests (Fig. 1d). In addition, the four level score (0–1, 2–4, 5–8, and 9–12) distribution of SLC39A6 protein expression in normal, precancerous lesions, and ESCC was significantly distinct (Fig. 1e). Furthermore, as shown in Table 2, in-depth analysis using the Chi square test revealed that the overexpression rates of SLC39A6 protein increased significantly in LGIN, HGIN, and ESCC compared with normal tissues (P < 0.001). Significant differences were also observed between LGIN and HGIN (P = 0.004), as well as between LGIN and ESCC (P = 0.037), whereas no significant differences were found between LGIN and ESCC (P > 0.05, Table 2). However, using the McNemar test, we did not found the SLC39A6 expression significantly differs between ESCC and their corresponding HGIN tissues (P = 0.076); similarly, the SLC39A6 expression also does not significantly differ between ESCC and their corresponding LGIN tissues (P = 0.229; Additional file 3: Table S2).Fig. 1

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