Abstract
Ovarian cancer (OVCA) is the most lethal gynecological cancer, due predominantly to late presentation, high recurrence rate and common chemoresistance development. The expression of the actin-associated protein cytosolic gelsolin (GSN) regulates the gynecological cancer cell fate resulting in dysregulation in chemosensitivity. In this study, we report that elevated expression of plasma gelsolin (pGSN), a secreted isoform of GSN and expressed from the same GSN gene, correlates with poorer overall survival and relapse-free survival in patients with OVCA. In addition, it is highly expressed and secreted in chemoresistant OVCA cells than its chemosensitive counterparts. pGSN, secreted and transported via exosomes (Ex-pGSN), upregulates HIF1α–mediated pGSN expression in chemoresistant OVCA cells in an autocrine manner as well as confers cisplatin resistance in otherwise chemosensitive OVCA cells. These findings support our hypothesis that exosomal pGSN promotes OVCA cell survival through both autocrine and paracrine mechanisms that transform chemosensitive cells to resistant counterparts. Specifically, pGSN transported via exosomes is a determinant of chemoresistance in OVCA.
Highlights
Chemoresistance is a major obstacle in the treatment of ovarian cancer (OVCA), one of the most fatal gynecological cancers
In the context of patients treated with platinum derivatives, we observed that elevated plasma gelsolin (pGSN) expression was associated with shorter progression-free survival (PFS) (14.9 months) compared with those with lower pGSN expression (PFS; 16.83 months) the difference was not significant
PGSN has been implicated in various inflammatory disorders, injuries and bacterial infections [23], whether and how it is involved in the regulation of chemosensitivity in OVCA is not known
Summary
Chemoresistance is a major obstacle in the treatment of ovarian cancer (OVCA), one of the most fatal gynecological cancers. We have recently shown that cGSN overexpression correlates with chemoresistance, poor prognosis, aggressive behavior, and cancer death [9], whereas the role of pGSN remain elusive. The secretion of EXs or MVs from cancer cells could regulate the functions of neighboring cells, including noncancerous or immune cells [17, 19,20,21]. EVs are believed to play a role in cancer progression, survival, and metastasis their participation in cellular basis of chemoresistance in OVCA remains largely unknown [17]. Whether EXs containing pGSN (Ex-pGSN) may be important in the regulation of chemosensitivity in neighboring OVCA cells has not been reported. We report for the first time pGSN secretion and transport via EXs, its functional interaction with HIF1α in an autocrine manner and conferring of cisplatin resistance in otherwise chemosensitive OVCA cells
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