TY - JOUR
T1 - Deciphering a GPCR-lncrna-miRNA nexus
T2 - Identification of an aberrant therapeutic target in ovarian cancer
AU - Ha, Ji Hee
AU - Radhakrishnan, Rangasudhagar
AU - Nadhan, Revathy
AU - Gomathinayagam, Rohini
AU - Jayaraman, Muralidharan
AU - Yan, Mingda
AU - Kashyap, Srishti
AU - Fung, Kar Ming
AU - Xu, Chao
AU - Bhattacharya, Resham
AU - Mukherjee, Priyabrata
AU - Isidoro, Ciro
AU - Song, Yong Sang
AU - Dhanasekaran, Danny N.
N1 - Publisher Copyright:
© 2024 Elsevier B.V.
PY - 2024/6/1
Y1 - 2024/6/1
N2 - 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.
AB - 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.
KW - GPCR
KW - High grade serous ovarian carcinoma
KW - Let-7 miRNAs
KW - Oncogenic pathways
KW - Ovarian cancer
KW - Therapy resistance
KW - UCA1
KW - lncRNA
UR - http://www.scopus.com/inward/record.url?scp=85191167555&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2024.216891
DO - 10.1016/j.canlet.2024.216891
M3 - Article
SN - 0304-3835
VL - 591
JO - Cancer Letters
JF - Cancer Letters
M1 - 216891
ER -