Introduction/Background PAR glycohydrolase (PARG) enzyme was found to play an essential role in the synthesis and hydrolysis of poly (ADP-ribose) (PAR), which play an important role in maintaining genomic integrity. Recently, PARG inhibitors were developed, however the effects of PARG in ovarian cancer treated-patients has not been evaluated yet. Here, we evaluate the effects of chemotherapy in PARG of high-grade serous ovarian cancer patients (HGSOC).
Methodology Two HGSOC cohorts were evaluated by immunohistochemistry: 54 chemo-naïve HGSOC patients (45 HGSOC, 9 borderline, 4 normal tissue) and 53 HGSOC chemo-treated patients (44 HGSOC, 9 borderline, 7 normal tissue). In addition, we used in silico analysis to evaluate the effect of PARG mRNA expression in ovarian cancer and its relation with patient outcome.
Results Our results showed that chemo-naïve patients have significant higher levels of PARG expression compared to borderline and normal (62.2%, 44.4% and 0% respectively). Interestingly, these levels were reduced significantly in HGSOC patient samples that have received chemotherapy (45.44%, 44%, 0%, respectively, p<0.03). Indeed, this demonstrated that chemotherapy induces a reduction in PARG expression to levels equal to the borderline tumors. Furthermore, we found a dramatic re-localization of PARG protein to the cytoplasm in chemo-treated patients (100%) compared with chemo-naïve HGSOC samples that were localized in the nucleus (80%, p<0.05). In silico analysis of 1500 ovarian cancer patients revealed that PARG is up-regulated in ovarian cancer in comparison with normal tissue and highly express in advance-metastatic HGSOC. Moreover, its expression in advance disease was associated with shorter overall survival.
Conclusion Our results showed that chemotherapy decreased PARG expression and re-localized it into the cytoplasm. Moreover, our findings highlights the possible use of PARG inhibitors as an adjuvant therapy to treat recurrent ovarian cancer together with chemotherapy and other new-targeted drugs such as PARP inhibitors.
Disclosure Nothing to disclose
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