Abstract
Ovarian cancer is a deadly gynecological malignancy with resistance to cisplatin a major clinical problem. We evaluated a role of long non-coding (lnc) RNA HOTTIP (HOXA transcript at the distal tip) in the cisplatin resistance of ovarian cancer cells, using paired cisplatin sensitive and resistant A2780 cells along with the SK-OV-3 cells. HOTTIP was significantly elevated in cisplatin resistant cells and its silencing reversed the cisplatin resistance of resistant cells. HOTTIP was found to sponge miR-205 and therefore HOTTIP silenced cells had higher levels of miR-205. Downregulation of miR-205 could attenuate HOTTIP-silencing effects whereas miR-205 upregulation in resistant cells was found to re-sensitize cells to cisplatin. HOTTIP silencing also led to reduced NF-κB activation, clonogenic potential and the reduced expression of stem cell markers SOX2, OCT4, and NANOG, an effect that could be attenuated by miR-205. Finally, ZEB2 was identified as the gene target of miR-205, thus completing the elucidation of HOTTIP-miR-205-ZEB2 as the novel axis which is functionally involved in the determination of cisplatin resistance in ovarian cancer cells.
Highlights
Ovarian cancers are a group of heterogenous malignancies and are one of the deadliest gynecological cancers with five-year survival close to or less than 50% (Torre et al, 2018)
To check if our hypothesis for the possible role of HOTTIP in cisplatin resistance of ovarian cancer cells was correct, we measured the levels of HOTTIP in a paired cell line model that comprised of cisplatin sensitive A2780 cells and their cisplatin resistance derivatives (A2780-CR)
We found that HOTTIP was expressed at significantly high levels in the resistant cells (Figure 1A) confirming our basic hypothesis
Summary
Ovarian cancers are a group of heterogenous malignancies and are one of the deadliest gynecological cancers with five-year survival close to or less than 50% (Torre et al, 2018). The heterogenous nature of ovarian cancer calls for novel studies to fully understand the disease etiology and identify novel targets of therapy. Clinical management of ovarian cancer involves the use of cisplatin (Bergamini et al, 2017) either alone or in combination with other drugs (Lee et al, 2020). Resistance to cisplatin is a common clinical observation in patients being treated with cisplatin (Yang et al, 2020). In the fight against ovarian cancer and in view of the importance of cisplatin in the treatment of ovarian cancer patients, a better understanding of resistance mechanisms will undoubtedly be important
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