Deciphering a GPCR-lncrna-miRNA nexus: Identification of an aberrant therapeutic target in ovarian cancer

Ji Hee Ha; Rangasudhagar Radhakrishnan; Revathy Nadhan; Rohini Gomathinayagam; Muralidharan Jayaraman; Mingda Yan; Srishti Kashyap; Kar-Ming Fung; Chao Xu; Resham Bhattacharya; Priyabrata Mukherjee; Ciro Isidoro; Yong Sang Song; Danny N Dhanasekaran

doi:10.1016/j.canlet.2024.216891

Deciphering a GPCR-lncrna-miRNA nexus: Identification of an aberrant therapeutic target in ovarian cancer

Cancer Lett. 2024 Apr 18:591:216891. doi: 10.1016/j.canlet.2024.216891. Online ahead of print.

Affiliations

¹ Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Department of Cell Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
² Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
³ Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
⁴ Department of Biostatistics and Epidemiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
⁵ Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
⁶ Department of Health Sciences, Università del Piemonte Orientale, Novara, Italy.
⁷ Seoul National University, College of Medicine, Seoul, 151-921, South Korea.
⁸ Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA; Department of Cell Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA. Electronic address: danny-dhanasekaran@ouhsc.edu.

PMID: 38642607
DOI: 10.1016/j.canlet.2024.216891

Abstract

Ovarian cancer ranks as a leading cause of mortality among gynecological malignancies, primarily due to the lack of early diagnostic tools, effective targeted therapy, and clear understanding of disease etiology. Previous studies have identified the pivotal role of Lysophosphatidic acid (LPA)-signaling in ovarian cancer pathobiology. Our earlier transcriptomic analysis identified Urothelial Carcinoma Associated-1 (UCA1) as an LPA-stimulated long non-coding RNA (lncRNA). In this study, we elucidate the tripartite interaction between LPA-signaling, UCA1, and let-7 miRNAs in ovarian cancer progression. Results show that the elevated expression of UCA1 enhances cell proliferation, invasive migration, and therapy resistance in high-grade serous ovarian carcinoma cells, whereas silencing UCA1 reverses these oncogenic phenotypes. UCA1 expression inversely correlates with survival outcomes and therapy response in ovarian cancer clinical samples, underscoring its prognostic significance. Mechanistically, UCA1 sequesters let-7 miRNAs, effectively neutralizing their tumor-suppressive functions involving key oncogenes such as Ras and c-Myc. More significantly, intratumoral delivery of UCA1-specific siRNAs inhibits the growth of cisplatin-refractory ovarian cancer xenografts, demonstrating the therapeutic potential of targeting LPAR-UCA1-let-7 axis in ovarian cancer. Thus, our results identify LPAR-UCA1-let-7 axis as a novel avenue for targeted treatment strategies.

Keywords: GPCR; High grade serous ovarian carcinoma; Let-7 miRNAs; Oncogenic pathways; Ovarian cancer; Therapy resistance; UCA1; lncRNA.