Cancers: Inhibition of LIFR Blocks Adiposity-Driven Endometrioid Endometrial Cancer Growth (Chen, Lai, Zheng)

by  Logan Blankenship
Uday P. Pratap
Xue Yang
Zexuan Liu
Kristin A. Altwegg
Bindu Santhamma
Kumaraguruparan Ramasamy
Swapna Konda
Yidong Chen
Zhao Lai
Siyuan Zheng
Gangadhara R. Sareddy
Philip T. Valente
Edward R. Kost
Hareesh B. Nair
Rajeshwar R. Tekmal
Ratna K. Vadlamudi
and Suryavathi Viswanadhapalli
Simple Summary
In this study, we utilized global RNA-seq to elucidate the molecular mechanisms by which obese conditions promote endometrioid endometrial cancer (EEC) progression. Our results suggest that obese conditions upregulate LIF/LIFR signaling, and EEC tumors collected from obese patients have high levels of LIF. Mechanistic studies suggest that LIF/LIFR signaling plays an important role in obesity-driven EEC progression. The LIFR inhibitor, EC359, can potentially suppress the tumor progression driven by increased adiposity found in obese patients.
Abstract
Endometrial cancer (EC) is the fourth most common cancer in women, and half of the endometrioid EC (EEC) cases are attributable to obesity. However, the underlying mechanism(s) of obesity-driven EEC remain(s) unclear. In this study, we examined whether LIF signaling plays a role in the obesity-driven progression of EEC. RNA-seq analysis of EEC cells stimulated by adipose conditioned medium (ADP-CM) showed upregulation of LIF/LIFR-mediated signaling pathways, including JAK/STAT and interleukin pathways. Immunohistochemistry analysis of normal and EEC tissues collected from obese patients revealed that LIF expression is upregulated in EEC tissues compared to the normal endometrium. Treatment of both primary and established EEC cells with ADP-CM increased the expression of LIF and its receptor LIFR and enhanced the proliferation of EEC cells. Treatment of EEC cells with the LIFR inhibitor EC359 abolished ADP-CM-induced colony formation and cell viability and decreased the growth of EEC organoids. Mechanistic studies using Western blotting, RT-qPCR, and reporter assays confirmed that ADP-CM activated LIF/LIFR downstream signaling, which can be effectively attenuated by the addition of EC359. In xenograft assays, co-implantation of adipocytes significantly enhanced EEC xenograft tumor growth. Further, treatment with EC359 significantly attenuated adipocyte-induced EEC progression in vivo. Collectively, our data support the premise that LIF/LIFR signaling plays an important role in obesity-driven EEC progression, and the LIFR inhibitor EC359 has the potential to suppress adipocyte-driven tumor progression.

Keywords: leukemia inhibitory factor; leukemia inhibitory factor receptor; endometrioid endometrial cancer; obesity; EC359; RNA-seq

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Article Categories: Research Paper