260 - Depletion of Alzheimer's-Associated Presenilin-1 Enhances Radiosensitivity of Hepatocellular Carcinoma
Presenter(s)
M. Q. Jia, X. Sui, H. Teng, and W. Wang; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing, China
Purpose/Objective(s): Radiotherapy has become an increasingly widespread modality for treating hepatocellular carcinoma (HCC), while radioresistance limits its efficacy. Presenilin-1 (PSEN1) was recognized for its role in Alzheimer's Disease and has been linked to proliferation in hematological malignancies, but its function in solid tumors and radioresistance remains unclear. We aim to explore its function and therapeutic potential in HCC.
Materials/Methods: We examined the expression pattern of PSEN1 in HCC with a tissue microarray staining consisting of 180 paired samples from 90 patients. Knockout and overexpression of PSEN1 in cell line was used to study its function. RNA sequencing and western blot identified and validated the associated molecular pathway. Clinical relevance was demonstrated in xenograft models.
Results: With whole-genome CRISPR-Cas9 screen and patient specimens, we identified PSEN1 as a driver of radioresistance and tumorigenesis in HCC. Kaplan-Meier survival analysis of TCGA-LIHC dataset demonstrated that high PSEN1 expression predicted poor prognosis in HCC patients. Higher PSEN1 expression in tumors than in adjacent normal tissues was detected in tissue microarray. Under 4Gy irradiation, knockout of PSEN1 caused a reduction in colony formation ability, cell viability and migration. RNA sequencing analysis on PSEN1 knockout cell strains showed that biological processes was mainly enriched in Negative Regulation Of Notch Signaling Pathway (GO: 0045746). Knockout of PSEN1 abolished cleavage of the Notch1 receptor, confirmed with impaired NICD Nuclear translocation. Combination treatment of PSEN1 inhibitor and radiotherapy significantly suppressed the tumor growth.
Conclusion: This evidence showed thatlPSEN1 regulates radiosensitivity of HCC by activating the Notch1 pathway. The combination of radiotherapy and PSEN1 inhibitors might be effective in HCC patients with radioresistance.