Phosphorylated p70S6K expression is an independent prognosticator for patients with esophageal squamous cell carcinoma.
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.


CONCLUSIONS
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.
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.
Shau-Hsuan
SH
Li
Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and the Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC.
Chang-Han
CH
Chen
Department of Thoracic & Cardiovascular Surgery, Kaohsiung Chang Gung Memorial Hospital and the Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC.
Hung-I
HI
Lu
Department of Pathology, Kaohsiung Chang Gung Memorial Hospital and the Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC.
Wan-Ting
WT
Huang
Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and the Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC.
Wan-Yu
WY
Tien
Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and the Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC.
Ya-Chun
YC
Lan
Department of Gastroenterology, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan, ROC.
Ching-Chang
CC
Lee
Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital and the Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC.
Yen-Hao
YH
Chen
Department of Thoracic & Cardiovascular Surgery, Kaohsiung Chang Gung Memorial Hospital and the Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC.
Hsuan-Ying
HY
Huang
Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and the Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC.
Alice Y W
AY
Chang
Department of Diagnostic Radiology, Kaohsiung Chang Gung Memorial Hospital and the Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC.
Wei-Che
WC
Lin
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D000068338:Everolimus; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D010766:Phosphorylation; D011379:Prognosis; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D000068338:Everolimus; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus