Shau-Hsuan Li1, Chang-Han Chen2, Hung-I Lu3, Wan-Ting Huang4, Wan-Yu Tien5, Ya-Chun Lan5, Ching-Chang Lee6, Yen-Hao Chen5, Hsuan-Ying Huang3, Alice Y W Chang2, Wei-Che Lin7. 1. Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and the Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC. Electronic address: lee.a0928@msa.hinet.net. 2. Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and the Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC. 3. Department of Thoracic & Cardiovascular Surgery, Kaohsiung Chang Gung Memorial Hospital and the Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC. 4. Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and the Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC. 5. Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and the Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC. 6. Department of Gastroenterology, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan, ROC. 7. Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital and the Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC.
Abstract
BACKGROUND: Although marked improvements have been made in surgical technique and chemoradiotherapy, the prognosis for patients with esophageal squamous cell carcinoma (ESCC) is still unsatisfactory. The mammalian target of rapamycin (mTOR) and its downstream signaling, p70 ribosomal S6 protein kinase (p70S6K) and eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), seem to play central roles in the regulation of cancer cell proliferation and survival. The significance of mTOR and its downstream targets, p70S6K and 4E-BP1, on the prognosis of ESCC remains uncertain, but this pathway is of particular concern because effective inhibitors are already available. METHODS: Immunohistochemistry performed to evaluate the expression of phosphorylated mTOR (p-mTOR), phosphorylated p70S6K (p-p70S6K), phosphorylated 4E-binding protein 1 (p-4E-BP1), and Ki-67 using 105 surgically resected ESCC correlated with treatment outcome. The effect of the mTOR signaling pathway inhibitor everolimus on ESCC cell lines were investigated in vitro by the 3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and in vivo by a nude mouse xenograft model. RESULTS: Univariate analysis showed that p-mTOR overexpression (P = .022), p-p70S6K overexpression (P = .002), and Ki-67 labeling index >50% (P = .045) were associated with inferior overall survival (OS). In a multivariate comparison, p-p70S6K overexpression (P = .001; hazard ratio, 2.247) remained independently associated with worse OS. In cell lines and the xenograft model, everolimus significantly inhibited ESCC growth. CONCLUSION: Overexpression of p-p70S6K is associated independently with a poor prognosis among patients with ESCC. The mTOR signaling pathway inhibitor everolimus can inhibit ESCC growth in vitro and in vivo. Our findings suggest that inhibition of mTOR signaling pathway may be a promising novel target for ESCC.
BACKGROUND: Although marked improvements have been made in surgical technique and chemoradiotherapy, the prognosis for patients with esophageal squamous cell carcinoma (ESCC) is still unsatisfactory. The mammalian target of rapamycin (mTOR) and its downstream signaling, p70 ribosomal S6 protein kinase (p70S6K) and eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1), seem to play central roles in the regulation of cancer cell proliferation and survival. The significance of mTOR and its downstream targets, p70S6K and 4E-BP1, on the prognosis of ESCC remains uncertain, but this pathway is of particular concern because effective inhibitors are already available. METHODS: Immunohistochemistry performed to evaluate the expression of phosphorylated mTOR (p-mTOR), phosphorylated p70S6K (p-p70S6K), phosphorylated 4E-binding protein 1 (p-4E-BP1), and Ki-67 using 105 surgically resected ESCC correlated with treatment outcome. The effect of the mTOR signaling pathway inhibitor everolimus on ESCC cell lines were investigated in vitro by the 3-(4.5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and in vivo by a nude mouse xenograft model. RESULTS: Univariate analysis showed that p-mTOR overexpression (P = .022), p-p70S6K overexpression (P = .002), and Ki-67 labeling index >50% (P = .045) were associated with inferior overall survival (OS). In a multivariate comparison, p-p70S6K overexpression (P = .001; hazard ratio, 2.247) remained independently associated with worse OS. In cell lines and the xenograft model, everolimus significantly inhibited ESCC growth. CONCLUSION: Overexpression of p-p70S6K is associated independently with a poor prognosis among patients with ESCC. The mTOR signaling pathway inhibitor everolimus can inhibit ESCC growth in vitro and in vivo. Our findings suggest that inhibition of mTOR signaling pathway may be a promising novel target for ESCC.
Authors: Peili Chen; Maria Mancini; Stephen T Sonis; Juan Fernandez-Martinez; Jing Liu; Ezra E W Cohen; F Gary Toback Journal: PLoS One Date: 2016-04-06 Impact factor: 3.240