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Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy
Published on: April 3, 2018
Identification of Rab27a as a host factor for oncolytic herpes virus susceptibility to tumor cells
XuSha Zhou1, Jing Zhao1, Yinglin Wu2
1Shenzhen International Institute for Biomedical Research, Shenzhen, 518110, Guangdong, China.
Abstract:
Oncolytic viruses are emerging as therapeutic agents in oncology. However, resistance of tumor cells to HSV oncolysis pose significant barriers to antitumor response. Thus, study on the mechanisms of therapeutic resistance to oHSV and finding strategies for overcoming these mechanisms are needed. In this study, Rab27a, a small GTPase involved in exosome biogenesis, was noticed to highly correlate with the susceptibility of tumor cells to oHSV. We found that i) lower abundance of Rab27a in oHSV resistant mouse tumor cells was shown when compared to that of sensitive tumor cells through deep-sequencing; ii) the resistance of human tumor cells to oHSV infection is associated with a downregulation of Rab27a expression and overexpression of Rab27a can promote the replication capacity of oHSV; iii) Interestingly, a stabilizer protein of Rab27a, KIBRA, highly accumulated in oHSV resistant tumor cells, which is in contrast with the expression pattern of Rab27a. Furthermore, knockdown of KIBRA expression reduced oHSV replication in oHSV resistant tumor cells. Consequently, Rab27a was found to be relevant with oHSV replication without cell type specificity, and low abundance of Rab27a contributes to oHSV resistance in both mouse and human tumor cells, which will give new insights in the identification of potential targets or biomarkers for oHSV cancer therapy.
Insights
Tumor cells resistant to oncolytic herpes simplex virus (oHSV) therapy show low levels of Rab27a. Restoring Rab27a expression may overcome resistance, offering new therapeutic strategies for cancer treatment.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Oncolytic viruses, specifically oncolytic herpes simplex virus (oHSV), are promising cancer therapeutics.
- Tumor cell resistance to oHSV poses a significant challenge to effective cancer treatment.
- Understanding the mechanisms of oHSV resistance is crucial for developing improved therapeutic strategies.
Purpose of the Study:
- To investigate the role of Rab27a, a protein involved in exosome biogenesis, in tumor cell susceptibility to oHSV.
- To identify potential biomarkers and therapeutic targets for overcoming oHSV resistance in cancer.
Main Methods:
- Deep-sequencing analysis of Rab27a abundance in oHSV-sensitive versus oHSV-resistant mouse tumor cells.
- Analysis of Rab27a expression in human tumor cells and its correlation with oHSV infection and replication.
- Investigating the impact of KIBRA, a Rab27a stabilizer, on oHSV resistance by assessing its expression and performing knockdown experiments.
Main Results:
- oHSV-resistant mouse tumor cells exhibited lower Rab27a abundance compared to sensitive cells.
- Downregulation of Rab27a expression correlated with resistance to oHSV infection in human tumor cells.
- Overexpression of Rab27a enhanced oHSV replication, while KIBRA accumulation in resistant cells counteracted this effect; KIBRA knockdown restored oHSV replication.
- Rab27a's role in oHSV replication is cell-type independent, with low abundance contributing to resistance.
Conclusions:
- Low Rab27a abundance is a key factor contributing to oHSV resistance in both mouse and human tumor cells.
- Rab27a is a critical determinant of oHSV replication efficacy.
- Targeting Rab27a or its regulatory proteins like KIBRA may represent a novel strategy to enhance oncolytic virus therapy for cancer.
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