Bcl-XL反义寡核苷酸转染对食管癌细胞系和裸鼠人食管癌移植瘤增殖、生长抑制作用的实验研究(英文)

Objective:The aim of our study was to investigate the biological effects of Bcl-XL antisense oligodeoxynucleotide(ASODN) transfected into cultured esophageal carcinoma cells and human esophageal carcinoma xenograft in nude mice.Methods:Cationic liposome-mediated ASODN was used to transfect esophageal carcinoma cells.RT-PCR, Western blot, MTT assay, flow cytometry, and in situ apoptosis cells detection(TUNEL detection) were used to systematically study the biological effects of transfected cells both in vitro and in vivo.Results:In this study, the results showed that the proliferation of esophageal carcinoma cells in ASODN group decreased significantly when compared with the control group(P < 0.05), at 57.3% Bcl-XL mRNA inhibitory rate, and a significant decreasing of Bcl-XL protein expression, at the apoptosis rates of(31.1 ± 5.8)% and 35.0% by flow cytometry and TUNEL assay respectively(P < 0.01, when compared with control groups).It also showed that the growth of human esophageal carcinoma in nude mice of ASODN group was significantly inhibited(P < 0.05), together with a significant decreased expression level of Bcl-XL mRNA and protein, and an induced tumor cell apoptosis in nude mice.Conclusion:Our result indicates Bcl-XL ASODN can effectively inhibit the proliferation of esophageal carcinoma cells in vitro and tumor growth in vivo.The suppression of Bcl-XL expression by ASODN may offer both a therapeutic approach and an important theoretic foundation for gene therapy against esophageal carcinoma.

RICTOR/mTORC2 affects tumorigenesis and therapeutic efficacy of mTOR inhibitors in esophageal squamous cell carcinoma

Dysregulation of mTORCl/mTORC2 pathway is observed in many cancers and mTORC1 inhibitors have been used clinically in many tumor types;however,the mechanism of mTORC2 in tumorigenesis is still obscure.Here,we mainly explored the potential role of mTORC2 in esophageal squamous cell carcinoma(ESCC)and its effects on the sensitivity of cells to mTOR inhibitors.We demonstrated that RICTOR,the key factor of mTORC2,and p-AKT(Ser473)were excessively activated in ESCC and their overexpression is related to lymph node metastasis and the tumor-node-metastasis(TNM)phase of ESCC patients.Furthermore,we found that mTORCl/mTORC2 inhibitor PP242 exhibited more efficacious anti-proliferative effect on ESCC cells than mTORC1 inhibitor RAD001 due to RAD001-triggered feedback activation of AKT signal.Another,we demonstrated that down-regulating expression of RICTOR in ECa109 and EC9706 cells inhibited proliferation and migration as well as induced cell cycle arrest and apoptosis.Noteworthy,knocking-down stably RICTOR significantly suppresses RAD001-induced feedback activation of AKT/PRAS40 signaling,and enhances inhibition efficacy of PP242 on the phosphorylation of AKT and PRAS40,thus potentiates the antitumor effect of RAD001 and PP242 both in vitro and in vivo.Our findings highlight that selective targeting mTORC2 could be a promising therapeutic strategy for future treatment of ESCC.