R-Spondin1/LGR5 Activates TGFβ Signaling and Suppresses Colon Cancer Metastasis

Abstract

Leucine rich repeat containing G protein-coupled receptor 5 (LGR5), an intestinal stem cell marker, is known to exhibit tumor suppressor activity in colon cancer, the mechanism of which is not understood. Here we show that R-spondin 1 (RSPO1)/LGR5 directly activates TGFβ signaling cooperatively with TGFβ type II receptor in colon cancer cells, enhancing TGFβ-mediated growth inhibition and stress-induced apoptosis. Knockdown of LGR5 attenuated downstream TGFβ signaling and increased cell proliferation, survival, and metastasis in an orthotopic model of colon cancer in vivo. Upon RSPO1 stimulation, LGR5 formed complexes with TGFβ receptors. Studies of patient specimens indicate that LGR5 expression was reduced in advanced stages and positively correlated with markers of TGFβ activation in colon cancer. Our study uncovers a novel crosstalk between LGR5 and TGFβ signaling in colon cancer and identifies LGR5 as a new modulator of TGFβ signaling able to suppress colon cancer metastasis.

Expression Profile of LGR5 and Its Prognostic Significance in Colorectal Cancer Progression

“…Moreover, most recent studies have shown a tumor-suppressive role of LGR5 signaling in human CRCs. 34,35 As RNA ISH is of only limited use for a practical purpose, the development of antibodies against LGR5 for immunohistochemistry analysis is required to confirm our findings and to reexamine the prognostic importance of LGR5 protein.…”

“…However, neither TGF-b 1 treatment nor EMT-TF overexpression reduced the LGR5 expression in LoVo cells; conversely, TGF-b 1 marginally increased LGR5 expression, which is consistent with a recent report demonstrating a positive correlation between LGR5 expression and TGF-b signaling. 35 Although tumor budding is closely related to EMT, whether in CRCs EMT-TFs are involved in the down-regulation of E-cadherin in budding cells is controversial. For example, Bronsert et al 46 In addition, although budding cells often showed abnormal E-cadherin expression, the majority of them still retained epithelial morphology, and vimentin expression was not detected in all of the cases in this study (Supplemental Figure S1), indicating that tumor budding may represent an EMT-like process but not a full EMT phenotype in CRCs.…”

The function of Piezo1 in colon cancer metastasis and its potential regulatory mechanism

“…Therefore, a deeper understanding of the molecular and cellular basis of metastasis is of high clinical significance (Rokavec et al 2017). Increasing evidence suggests that many molecular expression changes are involved in signal transduction pathways in colon cancer metastasis by affecting key molecular targets (Zhou et al 2017;Zykova et al 2018). Therefore, the identification of key molecular targets is of significant value for the diagnosis and treatment of patients with metastatic colon cancer.…”

Colon cancer therapy by focusing on colon cancer stem cells and their tumor microenvironment

“…Furthermore, various mutations of TGF‐β receptors (TGFBR1 and TGFBR2) and Smads like Smad2 and Smad4 are found in CCSCs (Bellam & Pasche, ). In 2017, Zhou et al () reported a cross‐talk between TGF‐β signaling and LGR5 in colon cancer cells and increased TGF‐β‐mediated growth inhibition and stress‐induced apoptosis by LGR5 (Zhou et al, ). Inhibition of stromal TGF‐β pathway blocks tumor metastasis in CRC.…”