Yi Lu

PGRN protects against serum deprivation-induced cell death by promoting the ROS scavenger system in cervical cancer

Abstract Progranulin (PGRN), an autocrine growth factor with tumorigenic roles in a variety of tumors, is a putative survival factor for normal and cancer cells in vitro. However, the fundamental mechanism of PGRN-mediated survival of cancer cells suffering from various types of microenvironmental stresses, such as serum deprivation, remains unknown. We show here that serum deprivation decreases intracellular PGRN protein levels in cervical cancer cells. PGRN protects cervical cancer cells against serum deprivation-induced apoptosis, limits reactive oxygen species (ROS) levels, maintains mitochondria integrity, and reduces oxidative damage of protein, lipid and DNA. PGRN enhances the ROS scavenger system, as evidenced by increased superoxide dismutase (SOD), catalase protein expression and activity, elevated GSH and NADPH levels and increased phase II detoxification enzyme expression in cervical cancer cells after serum withdrawal. The role of PGRN in ROS clearance is mediated by the PGRN-stimulated nuclear factor erythroid-derived 2-like 2 (NFE2L2)-antioxidant response element (ARE) pathway. Our study reveals an antioxidant role of PGRN in supporting the survival of cervical cancer cells under oxidative stress. This insight provides a new perspective on the how cervical cancer cells adapt to microenvironmental stress, contributing to cell viability and other malignant characteristics.

Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer

Abstract Background: Many loci have been found to be associated with risk of epithelial ovarian cancer (EOC). However, although there is considerable variation in progression-free survival (PFS), no loci have been found to be associated with outcome at genome-wide levels of significance. Methods: We carried out a genome-wide association study (GWAS) of PFS in 2,352 women with EOC who had undergone cytoreductive surgery and standard carboplatin/paclitaxel chemotherapy. Results: We found seven SNPs at 12q24.33 associated with PFS (P < 5 × 10–8), the top SNP being rs10794418 (HR = 1.24; 95% CI, 1.15–1.34; P = 1.47 × 10–8). High expression of a nearby gene, ULK1, is associated with shorter PFS in EOC, and with poor prognosis in other cancers. SNP rs10794418 is also associated with expression of ULK1 in ovarian tumors, with the allele associated with shorter PFS being associated with higher expression, and chromatin interactions were detected between the ULK1 promoter and associated SNPs in serous and endometrioid EOC cell lines. ULK1 knockout ovarian cancer cell lines showed significantly increased sensitivity to carboplatin in vitro. Conclusions: The locus at 12q24.33 represents one of the first genome-wide significant loci for survival for any cancer. ULK1 is a plausible candidate for the target of this association. Impact: This finding provides insight into genetic markers associated with EOC outcome and potential treatment options. See related commentary by Peres and Monteiro, p. 1604