lncRNA UCA1-Mediated Cdc42 Signaling Promotes Oncolytic Vaccinia Virus Cell-to-Cell Spread in Ovarian Cancer

Abstract

Oncolytic vaccinia virus (OVV) has demonstrated appropriate safety profiles for clinical development. Although designed to kill cancer cells efficiently, OVV sensitivity varies in individual cancers, and predictive biomarkers of therapeutic responses have not been identified. Here we found that OVV was much more efficient in KFTX paclitaxel-resistant ovarian cancer cells compared to that in KFlow paclitaxel-sensitive cells. Microarray analysis identified long non-coding RNA urothelial carcinoma-associated 1 (UCA1) upregulation, which contributed to both enhanced paclitaxel resistance and OVV spread. In addition, UCA1 expression correlated with efficient OVV spread in other ovarian cell lines and primary cancer cell cultures. When host pathways underlying OVV spread were analyzed, differences were detected in the activation of the Rho GTPase Cdc42, suggesting that filopodia formation enhances OVV cell-to-cell spread and tumor migration. Moreover, we established a clinically relevant mouse model of peritoneal metastasis using KFTX or KFlow cells. Paclitaxel exerted anti-tumor effects on KFlow, but not KFTX, tumors. In mice bearing KFTX cells after paclitaxel failure, OVV treatment induced the regression of residual tumors and improved survival. Our findings demonstrated that UCA1 promotes OVV cell-to-cell spread in ovarian cancer, resulting in enhanced therapeutic outcome.

Downregulated lncRNA UCA1 acts as ceRNA to adsorb microRNA-498 to repress proliferation, invasion and epithelial mesenchymal transition of esophageal cancer cells by decreasing ZEB2 expression

“…Long non-coding RNA urothelial carcinomaassociated 1 (UCA1) employs as an oncogene in different human cancers [6]. LncRNA UCA1 could promote cell growth and migration [7], which owns the potential to be a biomarker for the diagnoses of some cancers [8]. Jiao et al have found that lncRNA UCA1 is a significant molecular for tumor growth and could be an effective target for EC therapy [9].…”

Long Non-coding RNAs Involved in Resistance to Chemotherapy in Ovarian Cancer

“…UCA1 is also associated with resistance to Paclitaxel in OC (155,156), which can be reverted by UCA1 knockdown in cell lines (156). This effect was related to reduced sponging of miR-129 and, subsequently down-regulation of the ABCB1 gene that encodes an efflux pump previously correlated with multidrug resistance in cancer (156,157).…”

Targeting Long Non-coding RNA to Therapeutically Regulate Gene Expression in Cancer

“… 41 The classification of lncRNAs is based on the idea that RNAs with a base number greater than 200 nt can form various complex high-level structures, which can be distinguished from microRNAs (miRNAs). 42 In fact, however, when the base number of an RNA is 50–70 nt, some complex structures can be formed. 43 In addition to the linear structure, lncRNAs also have circular RNAs, which may be affected by the structure.…”