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Growth inhibition and chemo-radiosensitization of esophageal squamous cell carcinoma by survivin-shRNA lentivirus transfection.

ABSTRACT: Esophageal cancer is one of the most common types of cancer worldwide, and it has a poor prognosis. Chemo-radiotherapy resistance and cancer relapse are among the most difficult issues in its treatment. Identifying the underlying molecular mechanisms is critical for developing novel therapies. Survivin has been previously suggested to be overexpressed in esophageal cancer cells. The present study identified that down-regulation of survivin sensitized esophageal cancer cells to chemo-radiotherapy. Consistent with previous studies, the present study indicated that survivin was overexpressed in 4 esophageal squamous carcinoma cell lines. Short hairpin RNA delivered by lentivirus successfully knocked down survivin in these cancer cell lines. Consequently, down-regulation of survivin impaired their colony-forming, migratory and invasive capabilities, while the overexpression of survivin in normal human esophagus epithelial cells improved their resistance to cisplatin, paclitaxel and radiation. Survivin knockdown induced apoptosis in esophageal cancer KYSE-150 and ECA-109 cell lines when exposed to the aforementioned chemo-radiotherapy treatments. These results indicate that survivin expression sustains growth in esophageal cancer cells, and confers resistance to chemo-radiotherapy. Targeted survivin ablation may be a promising strategy against esophageal tumor relapse and chemo-radioresistance.

SUBMITTER: Zhou C

PROVIDER: S-EPMC6144918 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Growth inhibition and chemo-radiosensitization of esophageal squamous cell carcinoma by survivin-shRNA lentivirus transfection.

Zhou Changlin C Zhang Lin L Xu Peng P

Oncology letters 20180808 4

Esophageal cancer is one of the most common types of cancer worldwide, and it has a poor prognosis. Chemo-radiotherapy resistance and cancer relapse are among the most difficult issues in its treatment. Identifying the underlying molecular mechanisms is critical for developing novel therapies. Survivin has been previously suggested to be overexpressed in esophageal cancer cells. The present study identified that down-regulation of survivin sensitized esophageal cancer cells to chemo-radiotherapy ...[more]

PMID: 30250546

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Project description:Objective: Integrins have been shown to play an important role in the tumorigenesis of many cancers. In this work, we aimed to explore the expression and clinical value of Integrin α5β1 in esophageal squamous cell carcinoma (ESCC), and the effect of integrin β1 on the development and chemo-resistance of ESCC cells. Methods: The expression profiling of integrins was analyzed in the mRNA expression dataset of ESCC. The expression of Integrin α5β1 in 278 cases of ESCC tissues and 62 cases of paracancerous tissues was detected by immunohistochemistry (IHC). The association between the expression of Integrin α5β1 and the survival of ESCC patients was analyzed by Kaplan-Meier analysis. The effect of Integrin β1 on the proliferation, migration, and invasion of ESCC cells was examined by MTS, Transwell migration, and Transwell invasion assay. The effect of Integrin β1 and L1 cell adhesion molecule (L1CAM) on cisplatin resistance was detected by MTS and the signal pathways involved were analyzed by Western blotting. Results: Integrin β1 and Integrin α5 were significantly up-regulated in ESCC. High expression of Integrin β1 was also related to worse overall survival of ESCC patients and patients with low levels of both Integrin β1 and Integrin α5 showed the shortest survival. Results of IHC revealed that Integrin α5β1 was up-regulated in ESCC and its high expression was associated with poor prognosis and could serve as an independent prognostic factor. siRNA-mediated Integrin β1 silencing or antibody blocking restrained the proliferation, migration, and invasion of ESCC cells. Simultaneous knockdown of Integrin β1 and L1CAM reduced the cisplatin resistance of ESCC cells. Further studies showed that knockdown of Integrin β1 and L1CAM suppressed the activity of Akt signaling with or without cisplatin treatment. Moreover, dual high expression of Integrin β1 and L1CAM was related to worse overall survival of ESCC patients treated with preoperative chemotherapy. Conclusion: Integrin α5β1 was up-regulated in ESCC and could be used as a new prognostic indicator for ESCC patients. In addition, Integrin β1 was involved in the proliferation, invasion, and chemo-resistance of ESCC cells.

Project description:BackgroundThe efficacy of neoadjuvant chemo-immunotherapy (NAT) in esophageal squamous cell carcinoma (ESCC) is challenged by the intricate interplay within the tumor microenvironment (TME). Unveiling the immune landscape of ESCC in the context of NAT could shed light on heterogeneity and optimize therapeutic strategies for patients.MethodsWe analyzed single cells from 22 baseline and 24 post-NAT treatment samples of stage II/III ESCC patients to explore the association between the immune landscape and pathological response to neoadjuvant anti-PD-1 combination therapy, including pathological complete response (pCR), major pathological response (MPR), and incomplete pathological response (IPR).ResultsSingle-cell profiling identified 14 major cell subsets of cancer, immune, and stromal cells. Trajectory analysis unveiled an interesting link between cancer cell differentiation and pathological response to NAT. ESCC tumors enriched with less differentiated cancer cells exhibited a potentially favorable pathological response to NAT, while tumors enriched with clusters of more differentiated cancer cells may resist treatment. Deconvolution of transcriptomes in pre-treatment tumors identified gene signatures in response to NAT contributed by specific immune cell populations. Upregulated genes associated with better pathological responses in CD8 + effector T cells primarily involved interferon-gamma (IFNγ) signaling, neutrophil degranulation, and negative regulation of the T cell apoptotic process, whereas downregulated genes were dominated by those in the immune response-activating cell surface receptor signaling pathway. Natural killer cells in pre-treatment tumors from pCR patients showed a similar upregulation of gene expression in response to IFNγ but a downregulation of genes in the neutrophil-mediated immunity pathways. A decreased cellular contexture of regulatory T cells in ESCC TME indicated a potentially favorable pathological response to NAT. Cell-cell communication analysis revealed extensive interactions between CCL5 and its receptor CCR5 in various immune cells of baseline pCR tumors. Immune checkpoint interaction pairs, including CTLA4-CD86, TIGIT-PVR, LGALS9-HAVCR2, and TNFSF4-TNFRSF4, might serve as additional therapeutic targets for ICI therapy in ESCC.ConclusionsThis pioneering study unveiled an intriguing association between cancer cell differentiation and pathological response in esophageal cancer patients, revealing distinct subgroups of tumors for which neoadjuvant chemo-immunotherapy might be effective. We also delineated the immune landscape of ESCC tumors in the context of clinical response to NAT, which provides clinical insights for better understanding how patients respond to the treatment and further identifying novel therapeutic targets for ESCC patients in the future.

Dataset Information

Growth inhibition and chemo-radiosensitization of esophageal squamous cell carcinoma by survivin-shRNA lentivirus transfection.

Publications

Growth inhibition and chemo-radiosensitization of esophageal squamous cell carcinoma by survivin-shRNA lentivirus transfection.

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