Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario, Canada.
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal, Quebec, Canada.
J Clin Invest. 2021 Apr 1;131(7). doi: 10.1172/JCI142677.
Ovarian cancer (OC) is the most deadly gynecological malignancy, with unmet clinical need for new therapeutic approaches. The relaxin peptide is a pleiotropic hormone with reproductive functions in the ovary. Relaxin induces cell growth in several types of cancer, but the role of relaxin in OC is poorly understood. Here, using cell lines and xenograft models, we demonstrate that relaxin and its associated GPCR RXFP1 form an autocrine signaling loop essential for OC in vivo tumorigenesis, cell proliferation, and viability. We determined that relaxin signaling activates expression of prooncogenic pathways, including RHO, MAPK, Wnt, and Notch. We found that relaxin is detectable in patient-derived OC tumors, ascites, and serum. Further, inflammatory cytokines IL-6 and TNF-α activated transcription of relaxin via recruitment of STAT3 and NF-κB to the proximal promoter, initiating an autocrine feedback loop that potentiated expression. Inhibition of RXFP1 or relaxin increased cisplatin sensitivity of OC cell lines and abrogated in vivo tumor formation. Finally, we demonstrate that a relaxin-neutralizing antibody reduced OC cell viability and sensitized cells to cisplatin. Collectively, these data identify the relaxin/RXFP1 autocrine loop as a therapeutic vulnerability in OC.
卵巢癌 (OC) 是最致命的妇科恶性肿瘤，临床上迫切需要新的治疗方法。松弛肽是一种具有生殖功能的多功能激素，在卵巢中。松弛肽可诱导多种类型的癌症细胞生长，但松弛肽在 OC 中的作用知之甚少。在这里，我们使用细胞系和异种移植模型证明，松弛肽及其相关 GPCR RXFP1 形成了一种自分泌信号环路，对于体内 OC 肿瘤发生、细胞增殖和活力是必不可少的。我们确定松弛肽信号激活了致癌途径的表达，包括 RHO、MAPK、Wnt 和 Notch。我们发现松弛肽可在患者来源的 OC 肿瘤、腹水和血清中检测到。此外，炎性细胞因子 IL-6 和 TNF-α 通过募集 STAT3 和 NF-κB 到近端启动子来激活松弛肽的转录，启动自分泌反馈环，增强表达。抑制 RXFP1 或松弛肽增加了 OC 细胞系对顺铂的敏感性，并消除了体内肿瘤的形成。最后，我们证明松弛肽中和抗体降低了 OC 细胞的活力，并使细胞对顺铂敏感。总之，这些数据表明松弛肽/RXFP1 自分泌环是 OC 的治疗弱点。
