Int J Clin Exp Med 2015;8(8):14268-14276 www.ijcem.com /ISSN:1940-5901/IJCEM0011652
Original Article Gene expression profile of human esophageal squamous carcinoma cell line TE-1 Hong-Xing Cai1, Zheng-Qiu Zhu2, Xiao-Ming Sun1, Zhou-Ru Li1, Yan-Bo Chen1, Guo-Kai Dong1 Department of Forensic Medicine, Xuzhou Medical College, Xuzhou 221002, Jiangsu, P. R. China; 2The Affiliated Hospital of Xuzhou Medical College, Xuzhou 221002, Jiangsu, P. R. China 1
Received June 19, 2015; Accepted August 6, 2015; Epub August 15, 2015; Published August 30, 2015 Abstract: Esophageal squamous cell carcinoma (ESCC) is one of the most common and deadly causes of cancer worldwide. However, to date, the mechanisms underlying its pathogenesis remain unclear. The present study investigated the gene expression profile of human esophageal cancer cell line TE-1, a cell model for ESCC, to gain insight to the genetic regulation of this disease. Human esophageal cancer TE-1 cells and normal esophageal HET1A cells were cultured for isolation of total RNA. Differential expression of RNA transcripts was assessed using the Agilent 4×44 K microarray, combined with real-time PCR (qRT-PCR) for validation. Classification and function of the differential genes were illustrated by bioinformatics processing including hierarchical clustering and gene ontology (GO) analysis. We identified 4,986 transcripts with differential expression (fold-change ≥1.5, P7 and P7 and P5% associated with cell components. C. GO analysis of genes >5% associated with molecular functions.
GO and pathway analysis Inputting differentially expressed transcripts into the online tool David 6.7 (http://david. abcc.ncifcrf.gov/home.jsp) sorted 340 terms belonging to biological processes, 124 terms belonging to cellular components, and 104 terms belonging to molecular functions (Figure
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1). Molecular functions included RNA binding, nucleotide binding, enzyme binding, cofactor binding, structural ribosome constituents, and ATP binding, and these functions could be associated with the occurrence and development of ESCC. Pathway analysis revealed 35 different pathways related to differentially expressed genes (Table 4).
Int J Clin Exp Med 2015;8(8):14268-14276
Gene expression of ESCC TE1 Table 4. Target gene-related pathways Counts 40 30 28 47 34 22 49 23 32 45
% 0.90 0.67 0.63 1.05 0.76 0.49 1.10 0.52 0.72 1.01
P-value 0.0000 0.0003 0.0004 0.0005 0.0007 0.0009 0.0010 0.0029 0.0056 0.0074
Chronic myeloid leukemia Cell cycle Neurotrophin signaling pathway Huntington disease Inositol phosphate metabolism Alzheimer’s disease Pathways in cancer Propanoate metabolism Phosphatidylinositol signaling system N-glycan biosynthesis Limonene and pinene degradation Prostate cancer Pancreatic cancer Parkinson’s disease Nicotinate and nicotinamide metabolism mTOR signaling pathway
28 42 41 56 21 51 93 14 26 18 8 30 25 40 11 19
0.63 0.94 0.92 1.25 0.47 1.14 2.08 0.31 0.58 0.40 0.18 0.67 0.56 0.90 0.25 0.43
0.0080 0.0084 0.0124 0.0127 0.0150 0.0158 0.0202 0.0208 0.0243 0.0244 0.0258 0.0265 0.0316 0.0338 0.0339 0.0406
Beta-alanine metabolism Apoptosis Pyrimidine metabolism NOD-like receptor signaling pathway Amino sugar and nucleotide sugar metabolism Lysine degradation Valine, leucine, and isoleucine degradation MAPK signaling pathway Folate biosynthesis
10 28 30 21 16 16 16 73 6
0.22 0.63 0.67 0.47 0.36 0.36 0.36 1.64 0.13
0.0488 0.0563 0.0598 0.0645 0.0662 0.0662 0.0662 0.0793 0.0877
Term Ribosome p53 signaling pathway Glioma Spliceosome Small cell lung cancer Proteasome Ubiquitin mediated proteolysis Non-small cell lung cancer ErbB signaling pathway Insulin signaling pathway
qPCR confirmation of mRNA expression To verify microarray results, five top up-regulated and five top down-regulated mRNAs were amplified using qPCR. Results showed highly significant concordance with microarray results for all 10 transcripts (Figure 2). Discussion We have presented a detailed analysis of the mRNA profile of esophageal cancer cell line
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TE-1 in comparison with the normal esophageal cell line HET-1A. These results have implications for our understanding of esophageal tumorigenesis. The cDNA microarray used in this study has 27,958 Entrez gene RNA targets, of which 4,986 were differentially expressed between TE-1 esophageal cancer cells and HET-1A normal esophageal cells. Some of these genes have already been demonstrated to be relevant in esophageal cancer. For example, HOXC6 and HOXC8 are prognostic markers in patients with ESCC [9]. GPCR56, an orphan G-protein coupled receptor, is detected in 48% of ESCCs, while adjacent nonmalignant esophageal tissue does not express this transcript [10]. Expression of Hsp90α and cyclin B1 is associated with tumor malignancy and prognosis for patients with ESCC [11]. Further exploration of differentially expressed genes in the progression of esophageal cancer is warranted to explore potential early diagnostic markers and their functions in esophageal tumorigenesis.
GO has become a major bioinformatics initiative to unify the representation of genes and gene products. Ontology is divided into three domains: (1) cellular components, referring to the parts of a cell or its extracellular environment; (2) molecular functions, describing the elemental activities of a gene product at the molecular level; and (3) biological processes, defining molecular events pertinent to the function of integrated living cells, tissues, organs, and organisms. This study sorted differentially expressed transcripts and identified 340 terms indexed in biological processes, 124 terms indexed in cellular components, and 104 terms indexed in molecular functions. Further, more
Int J Clin Exp Med 2015;8(8):14268-14276
Gene expression of ESCC TE1
Figure 2. Quantitative real-time PCR (qPCR) confirmed expression of ten selected genes. Five up-regulated genes [LOC643650 (LOC643650); tuftelin 1 (TUFT1); histone cluster 1, H2bk (HIST1H2BK); G protein-coupled receptor 119 (GPR119); and chromosome 10 open reading frame 35 (C10orf35)] and five down-regulated genes [AT rich interactive domain 3B (ARID3B); THAP domain containing 10 (THAP10); pseudouridylate synthase 7 homolog (PUS7); IKAROS family zinc finger 4 (IKZF4); and dispatched homolog 2 (DISP2)] were amplified from esophageal cancer cell line TE-1 and control esophageal cell line HET-1A. mRNA expression was measured in triplicate by qPCR and normalized to expression of housekeeping gene U6 using the two standard curves method. Data are expressed as mean ± SEM.
than ten terms were >5% involved in biological processes: cellular macromolecule catabolic processes (5.49%); macromolecule catabolic processes (5.67%); cell cycle (5.33%); transcription (12.86%); negative regulation of macromolecule metabolic processes (5.02%); regulation of transcription (14.97%); protein localization (5.47%); proteolysis (6.25%); regulation of RNA metabolic processes (10.24%); and DNA-dependence (9.88%).
College, No. 209, Tongshan Road, Xuzhou 221002, Jiangsu Province, P. R. China. E-mail: yccaihx1962@ 126.com
Further analysis revealed these differentially expressed transcripts were associated with 35 pathways. Among them, p53 signaling [12], glioma [13], ubiquitin-mediated proteolysis [14], insulin signaling [15], cell cycle [16], inositol phosphate metabolism [17], mTOR signaling [18], and MAPK signaling [19] have been demonstrated to be associated with the occurrence and development of human esophageal cancer, but little is known for the other pathways, which should be explored in human esophageal cancer in the future.
[3]
References [1] [2]
[4]
[5]
Disclosure of conflict of interest None. Address correspondence to: Dr. Hong-Xing Cai, Department of Forensic Medicine, Xuzhou Medical
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[6]
Zhang Y. Epidemiology of esophageal cancer. World J Gastroenterol 2013; 19: 5598-5606. Yingsong L, Yukari T, Yutong H, Shogo K, Youlin Q, Junko U, Wenqiang W, Manami I, Hideo T. Epidemiology of esophageal cancer in Japan and China. J Epidemiol 2013; 23: 233-242. Tong HX, Zhou YH, Hou YY, Zhang Y, Huang Y, Xie B, Wang JY, Jiang Q, He JY, Shao YB, Han WM, Tan RY, Zhu J, Lu WQ. Expression profile of microRNAs in gastrointestinal stromal tumors revealed by high throughput quantitative RTPCR microarray. World J Gastroenterol 2015; 21: 5843-5855. Chen C, Li Z, Yang Y, Xiang T, Song W, Liu S. Microarray expression profiling of dysregulated long non-coding RNAs in triple-negative breast cancer. Cancer Biol Ther 2015; 16: 856-65. Chong GO, Jeon HS, Han HS, Son JW, Lee YH, Hong DG, Lee YS, Cho YL. Differential microRNA expression profiles in primary and recurrent epithelial ovarian cancer. Anticancer Res 2015; 35: 2622-2617. Schulten HJ, Al-Mansouri Z, Baghallab I, Bagatian N, Subhi O, Karim S, Al-Aradati H, AlMutawa A, Johary A, Meccawy AA, Al-Ghamdi K, Al-Hamour O, Al-Qahtani M, Al-Maghrabi J. Comparison of microarray expression profiles
Int J Clin Exp Med 2015;8(8):14268-14276
Gene expression of ESCC TE1
[7] [8]
[9]
[10]
[11]
[12] [13]
between follicular variant of papillary thyroid carcinomas and follicular adenomas of the thyroid. BMC Genomics 2015; 16: S7. Guo W, Jiang YG. Current gene expression studies in esophageal carcinoma. Curr Genomics 2009; 10: 534-539. Li BQ, Xu J, Li QZ, Li XY, Gu FZ, Mu XL. A study on cell biological characters of human esophageal cancer cell line TE-1. Chinese Journal of Modern Medicine 2011; 13: 33-35. Du YB, Dong B, Shen LY, Yan WP, Dai L, Xiong HC, Liang Z, Kang XZ, Qin B, Chen KN. The survival predictive significance of HOXC6 and HOXC8 in esophageal squamous cell carcinoma. J Surg Res 2014; 188: 442-450. Sud N, Sharma R, Ray R, Chattopadhyay TK, Ralhan R. Differential expression of G-protein coupled receptor 56 in human esophageal squamous cell carcinoma. Cancer Lett 2006; 233: 265-270. Huang T, Chen S, Han H, Li H, Huang Z, Zhang J, Yin Q, Wang X, Ma X, Dai P, Duan D, Zou F, Chen X. Expression of Hsp 90a and cyclin B1 were related to prognosis of esophageal squamous cell carcinoma and keratin peral formation. Int J Clin Exp Pathol 2014; 7: 1544-1552. Dent P. Non-canonical p53 signaling to promote invasion. Cancer Biol Ther 2013; 14: 879-880. Min S, Xiaoyan X, Fnaghui P, Yamei W, Xiaoli Y, Feng W. The glioma-associated oncogene homolog 1 promotes epithelial-mesenchymal transition in human esophageal squamous cell cancer by inhibiting E-cadherin via Snail. Cancer Gene Ther 2013; 20: 379-385.
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[14] Issaenko OA, Bitterman PB, Polunovsky VA, Dahlberg PS. Cap-dependent mRNA translation and the ubiquitin-proteasome system cooperate to promote ERBB2-dependent esophageal cancer phenotype. Cancer Gene Ther 2012; 19: 609-618. [15] Yang Y, Wen F, Dang L, Fan Y, Liu D, Wu K, Zhao S. Insulin enhances apoptosis induced by cisplatin in human esophageal squamous cell carcinoma EC9706 cells related to inhibition of autophagy. Chin Med J (Engl) 2014; 127: 353358. [16] Shi Z, Tang Y, Li K, Fan Q. TKTL1 expression and its downregulation is implicated in cell proliferation inhibition and cell cycle arrest in esophageal squamous cell carcinoma. Tumour Biol 2015; [Epub ahead of print]. [17] Tan J, Yu CY, Wang ZH, Chen HY, Guan J, Chen YX, Fang JY. Genetic variants in the inositol phosphate metabolism pathway and risk of different types of cancer. Sci Rep 2015; 5: 8473. [18] Hou G, Yang S, Zhou Y, Wang C, Zhao W, Lu Z. Targeted inhibition of mTOR signaling improves sensitivity of esophageal squamous cell carcinoma cells to cisplatin. J Immunol Res 2014; 2014: 845763. [19] Zheng ST, Huo Q, Tuerxun A, Ma WJ, Lv GD, Huang CG, Liu Q, Wang X, Lin RY, Sheyhidin I, Lu XM. The expression and activation of ERK/ MAPK pathway in human esophageal cancer cell line EC9706. Mol Biol Rep 2011; 38: 865872.
Int J Clin Exp Med 2015;8(8):14268-14276
Original Article Gene expression profile of human esophageal squamous carcinoma cell line TE-1 Hong-Xing Cai1, Zheng-Qiu Zhu2, Xiao-Ming Sun1, Zhou-Ru Li1, Yan-Bo Chen1, Guo-Kai Dong1 Department of Forensic Medicine, Xuzhou Medical College, Xuzhou 221002, Jiangsu, P. R. China; 2The Affiliated Hospital of Xuzhou Medical College, Xuzhou 221002, Jiangsu, P. R. China 1
Received June 19, 2015; Accepted August 6, 2015; Epub August 15, 2015; Published August 30, 2015 Abstract: Esophageal squamous cell carcinoma (ESCC) is one of the most common and deadly causes of cancer worldwide. However, to date, the mechanisms underlying its pathogenesis remain unclear. The present study investigated the gene expression profile of human esophageal cancer cell line TE-1, a cell model for ESCC, to gain insight to the genetic regulation of this disease. Human esophageal cancer TE-1 cells and normal esophageal HET1A cells were cultured for isolation of total RNA. Differential expression of RNA transcripts was assessed using the Agilent 4×44 K microarray, combined with real-time PCR (qRT-PCR) for validation. Classification and function of the differential genes were illustrated by bioinformatics processing including hierarchical clustering and gene ontology (GO) analysis. We identified 4,986 transcripts with differential expression (fold-change ≥1.5, P7 and P7 and P5% associated with cell components. C. GO analysis of genes >5% associated with molecular functions.
GO and pathway analysis Inputting differentially expressed transcripts into the online tool David 6.7 (http://david. abcc.ncifcrf.gov/home.jsp) sorted 340 terms belonging to biological processes, 124 terms belonging to cellular components, and 104 terms belonging to molecular functions (Figure
14273
1). Molecular functions included RNA binding, nucleotide binding, enzyme binding, cofactor binding, structural ribosome constituents, and ATP binding, and these functions could be associated with the occurrence and development of ESCC. Pathway analysis revealed 35 different pathways related to differentially expressed genes (Table 4).
Int J Clin Exp Med 2015;8(8):14268-14276
Gene expression of ESCC TE1 Table 4. Target gene-related pathways Counts 40 30 28 47 34 22 49 23 32 45
% 0.90 0.67 0.63 1.05 0.76 0.49 1.10 0.52 0.72 1.01
P-value 0.0000 0.0003 0.0004 0.0005 0.0007 0.0009 0.0010 0.0029 0.0056 0.0074
Chronic myeloid leukemia Cell cycle Neurotrophin signaling pathway Huntington disease Inositol phosphate metabolism Alzheimer’s disease Pathways in cancer Propanoate metabolism Phosphatidylinositol signaling system N-glycan biosynthesis Limonene and pinene degradation Prostate cancer Pancreatic cancer Parkinson’s disease Nicotinate and nicotinamide metabolism mTOR signaling pathway
28 42 41 56 21 51 93 14 26 18 8 30 25 40 11 19
0.63 0.94 0.92 1.25 0.47 1.14 2.08 0.31 0.58 0.40 0.18 0.67 0.56 0.90 0.25 0.43
0.0080 0.0084 0.0124 0.0127 0.0150 0.0158 0.0202 0.0208 0.0243 0.0244 0.0258 0.0265 0.0316 0.0338 0.0339 0.0406
Beta-alanine metabolism Apoptosis Pyrimidine metabolism NOD-like receptor signaling pathway Amino sugar and nucleotide sugar metabolism Lysine degradation Valine, leucine, and isoleucine degradation MAPK signaling pathway Folate biosynthesis
10 28 30 21 16 16 16 73 6
0.22 0.63 0.67 0.47 0.36 0.36 0.36 1.64 0.13
0.0488 0.0563 0.0598 0.0645 0.0662 0.0662 0.0662 0.0793 0.0877
Term Ribosome p53 signaling pathway Glioma Spliceosome Small cell lung cancer Proteasome Ubiquitin mediated proteolysis Non-small cell lung cancer ErbB signaling pathway Insulin signaling pathway
qPCR confirmation of mRNA expression To verify microarray results, five top up-regulated and five top down-regulated mRNAs were amplified using qPCR. Results showed highly significant concordance with microarray results for all 10 transcripts (Figure 2). Discussion We have presented a detailed analysis of the mRNA profile of esophageal cancer cell line
14274
TE-1 in comparison with the normal esophageal cell line HET-1A. These results have implications for our understanding of esophageal tumorigenesis. The cDNA microarray used in this study has 27,958 Entrez gene RNA targets, of which 4,986 were differentially expressed between TE-1 esophageal cancer cells and HET-1A normal esophageal cells. Some of these genes have already been demonstrated to be relevant in esophageal cancer. For example, HOXC6 and HOXC8 are prognostic markers in patients with ESCC [9]. GPCR56, an orphan G-protein coupled receptor, is detected in 48% of ESCCs, while adjacent nonmalignant esophageal tissue does not express this transcript [10]. Expression of Hsp90α and cyclin B1 is associated with tumor malignancy and prognosis for patients with ESCC [11]. Further exploration of differentially expressed genes in the progression of esophageal cancer is warranted to explore potential early diagnostic markers and their functions in esophageal tumorigenesis.
GO has become a major bioinformatics initiative to unify the representation of genes and gene products. Ontology is divided into three domains: (1) cellular components, referring to the parts of a cell or its extracellular environment; (2) molecular functions, describing the elemental activities of a gene product at the molecular level; and (3) biological processes, defining molecular events pertinent to the function of integrated living cells, tissues, organs, and organisms. This study sorted differentially expressed transcripts and identified 340 terms indexed in biological processes, 124 terms indexed in cellular components, and 104 terms indexed in molecular functions. Further, more
Int J Clin Exp Med 2015;8(8):14268-14276
Gene expression of ESCC TE1
Figure 2. Quantitative real-time PCR (qPCR) confirmed expression of ten selected genes. Five up-regulated genes [LOC643650 (LOC643650); tuftelin 1 (TUFT1); histone cluster 1, H2bk (HIST1H2BK); G protein-coupled receptor 119 (GPR119); and chromosome 10 open reading frame 35 (C10orf35)] and five down-regulated genes [AT rich interactive domain 3B (ARID3B); THAP domain containing 10 (THAP10); pseudouridylate synthase 7 homolog (PUS7); IKAROS family zinc finger 4 (IKZF4); and dispatched homolog 2 (DISP2)] were amplified from esophageal cancer cell line TE-1 and control esophageal cell line HET-1A. mRNA expression was measured in triplicate by qPCR and normalized to expression of housekeeping gene U6 using the two standard curves method. Data are expressed as mean ± SEM.
than ten terms were >5% involved in biological processes: cellular macromolecule catabolic processes (5.49%); macromolecule catabolic processes (5.67%); cell cycle (5.33%); transcription (12.86%); negative regulation of macromolecule metabolic processes (5.02%); regulation of transcription (14.97%); protein localization (5.47%); proteolysis (6.25%); regulation of RNA metabolic processes (10.24%); and DNA-dependence (9.88%).
College, No. 209, Tongshan Road, Xuzhou 221002, Jiangsu Province, P. R. China. E-mail: yccaihx1962@ 126.com
Further analysis revealed these differentially expressed transcripts were associated with 35 pathways. Among them, p53 signaling [12], glioma [13], ubiquitin-mediated proteolysis [14], insulin signaling [15], cell cycle [16], inositol phosphate metabolism [17], mTOR signaling [18], and MAPK signaling [19] have been demonstrated to be associated with the occurrence and development of human esophageal cancer, but little is known for the other pathways, which should be explored in human esophageal cancer in the future.
[3]
References [1] [2]
[4]
[5]
Disclosure of conflict of interest None. Address correspondence to: Dr. Hong-Xing Cai, Department of Forensic Medicine, Xuzhou Medical
14275
[6]
Zhang Y. Epidemiology of esophageal cancer. World J Gastroenterol 2013; 19: 5598-5606. Yingsong L, Yukari T, Yutong H, Shogo K, Youlin Q, Junko U, Wenqiang W, Manami I, Hideo T. Epidemiology of esophageal cancer in Japan and China. J Epidemiol 2013; 23: 233-242. Tong HX, Zhou YH, Hou YY, Zhang Y, Huang Y, Xie B, Wang JY, Jiang Q, He JY, Shao YB, Han WM, Tan RY, Zhu J, Lu WQ. Expression profile of microRNAs in gastrointestinal stromal tumors revealed by high throughput quantitative RTPCR microarray. World J Gastroenterol 2015; 21: 5843-5855. Chen C, Li Z, Yang Y, Xiang T, Song W, Liu S. Microarray expression profiling of dysregulated long non-coding RNAs in triple-negative breast cancer. Cancer Biol Ther 2015; 16: 856-65. Chong GO, Jeon HS, Han HS, Son JW, Lee YH, Hong DG, Lee YS, Cho YL. Differential microRNA expression profiles in primary and recurrent epithelial ovarian cancer. Anticancer Res 2015; 35: 2622-2617. Schulten HJ, Al-Mansouri Z, Baghallab I, Bagatian N, Subhi O, Karim S, Al-Aradati H, AlMutawa A, Johary A, Meccawy AA, Al-Ghamdi K, Al-Hamour O, Al-Qahtani M, Al-Maghrabi J. Comparison of microarray expression profiles
Int J Clin Exp Med 2015;8(8):14268-14276
Gene expression of ESCC TE1
[7] [8]
[9]
[10]
[11]
[12] [13]
between follicular variant of papillary thyroid carcinomas and follicular adenomas of the thyroid. BMC Genomics 2015; 16: S7. Guo W, Jiang YG. Current gene expression studies in esophageal carcinoma. Curr Genomics 2009; 10: 534-539. Li BQ, Xu J, Li QZ, Li XY, Gu FZ, Mu XL. A study on cell biological characters of human esophageal cancer cell line TE-1. Chinese Journal of Modern Medicine 2011; 13: 33-35. Du YB, Dong B, Shen LY, Yan WP, Dai L, Xiong HC, Liang Z, Kang XZ, Qin B, Chen KN. The survival predictive significance of HOXC6 and HOXC8 in esophageal squamous cell carcinoma. J Surg Res 2014; 188: 442-450. Sud N, Sharma R, Ray R, Chattopadhyay TK, Ralhan R. Differential expression of G-protein coupled receptor 56 in human esophageal squamous cell carcinoma. Cancer Lett 2006; 233: 265-270. Huang T, Chen S, Han H, Li H, Huang Z, Zhang J, Yin Q, Wang X, Ma X, Dai P, Duan D, Zou F, Chen X. Expression of Hsp 90a and cyclin B1 were related to prognosis of esophageal squamous cell carcinoma and keratin peral formation. Int J Clin Exp Pathol 2014; 7: 1544-1552. Dent P. Non-canonical p53 signaling to promote invasion. Cancer Biol Ther 2013; 14: 879-880. Min S, Xiaoyan X, Fnaghui P, Yamei W, Xiaoli Y, Feng W. The glioma-associated oncogene homolog 1 promotes epithelial-mesenchymal transition in human esophageal squamous cell cancer by inhibiting E-cadherin via Snail. Cancer Gene Ther 2013; 20: 379-385.
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[14] Issaenko OA, Bitterman PB, Polunovsky VA, Dahlberg PS. Cap-dependent mRNA translation and the ubiquitin-proteasome system cooperate to promote ERBB2-dependent esophageal cancer phenotype. Cancer Gene Ther 2012; 19: 609-618. [15] Yang Y, Wen F, Dang L, Fan Y, Liu D, Wu K, Zhao S. Insulin enhances apoptosis induced by cisplatin in human esophageal squamous cell carcinoma EC9706 cells related to inhibition of autophagy. Chin Med J (Engl) 2014; 127: 353358. [16] Shi Z, Tang Y, Li K, Fan Q. TKTL1 expression and its downregulation is implicated in cell proliferation inhibition and cell cycle arrest in esophageal squamous cell carcinoma. Tumour Biol 2015; [Epub ahead of print]. [17] Tan J, Yu CY, Wang ZH, Chen HY, Guan J, Chen YX, Fang JY. Genetic variants in the inositol phosphate metabolism pathway and risk of different types of cancer. Sci Rep 2015; 5: 8473. [18] Hou G, Yang S, Zhou Y, Wang C, Zhao W, Lu Z. Targeted inhibition of mTOR signaling improves sensitivity of esophageal squamous cell carcinoma cells to cisplatin. J Immunol Res 2014; 2014: 845763. [19] Zheng ST, Huo Q, Tuerxun A, Ma WJ, Lv GD, Huang CG, Liu Q, Wang X, Lin RY, Sheyhidin I, Lu XM. The expression and activation of ERK/ MAPK pathway in human esophageal cancer cell line EC9706. Mol Biol Rep 2011; 38: 865872.
Int J Clin Exp Med 2015;8(8):14268-14276
