R-Spondin1/LGR5 activates TGFβ signaling and suppresses colon cancer metastasis

Xiaolin Zhou; Liying Geng; Degeng Wang; Haowei Yi; Geoffrey Talmon; Jing Wang

doi:10.1158/0008-5472.CAN-17-0219

R-Spondin1/LGR5 activates TGFβ signaling and suppresses colon cancer metastasis

Xiaolin Zhou, Liying Geng, Degeng Wang, Haowei Yi, Geoffrey Talmon, Jing Wang

Environmental Toxicology

Research output: Contribution to journal › Article › peer-review

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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 TGFb signaling cooperatively with TGFb type II receptor in colon cancer cells, enhancing TGFb-mediated growth inhibition and stress-induced apoptosis. Knockdown of LGR5 attenuated downstream TGFb signaling and increased cell proliferation, survival, and metastasis in an orthotopic model of colon cancer in vivo. Upon RSPO1 stimulation, LGR5 formed complexes with TGFb receptors. Studies of patient specimens indicate that LGR5 expression was reduced in advanced stages and positively correlated with markers of TGFb activation in colon cancer. Our study uncovers a novel cross-talk between LGR5 and TGFβ signaling in colon cancer and identifies LGR5 as a new modulator of TGFβ signaling able to suppress colon cancer metastasis.

Original language	English
Pages (from-to)	6589-6602
Number of pages	14
Journal	Cancer Research
Volume	77
Issue number	23
DOIs	https://doi.org/10.1158/0008-5472.CAN-17-0219
State	Published - Dec 1 2017

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title = "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 TGFb signaling cooperatively with TGFb type II receptor in colon cancer cells, enhancing TGFb-mediated growth inhibition and stress-induced apoptosis. Knockdown of LGR5 attenuated downstream TGFb signaling and increased cell proliferation, survival, and metastasis in an orthotopic model of colon cancer in vivo. Upon RSPO1 stimulation, LGR5 formed complexes with TGFb receptors. Studies of patient specimens indicate that LGR5 expression was reduced in advanced stages and positively correlated with markers of TGFb activation in colon cancer. Our study uncovers a novel cross-talk between LGR5 and TGFβ signaling in colon cancer and identifies LGR5 as a new modulator of TGFβ signaling able to suppress colon cancer metastasis.",

author = "Xiaolin Zhou and Liying Geng and Degeng Wang and Haowei Yi and Geoffrey Talmon and Jing Wang",

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T1 - R-Spondin1/LGR5 activates TGFβ signaling and suppresses colon cancer metastasis

AU - Zhou, Xiaolin

AU - Geng, Liying

AU - Wang, Degeng

AU - Yi, Haowei

AU - Talmon, Geoffrey

AU - Wang, Jing

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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 TGFb signaling cooperatively with TGFb type II receptor in colon cancer cells, enhancing TGFb-mediated growth inhibition and stress-induced apoptosis. Knockdown of LGR5 attenuated downstream TGFb signaling and increased cell proliferation, survival, and metastasis in an orthotopic model of colon cancer in vivo. Upon RSPO1 stimulation, LGR5 formed complexes with TGFb receptors. Studies of patient specimens indicate that LGR5 expression was reduced in advanced stages and positively correlated with markers of TGFb activation in colon cancer. Our study uncovers a novel cross-talk between LGR5 and TGFβ signaling in colon cancer and identifies LGR5 as a new modulator of TGFβ signaling able to suppress colon cancer metastasis.

AB - 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 TGFb signaling cooperatively with TGFb type II receptor in colon cancer cells, enhancing TGFb-mediated growth inhibition and stress-induced apoptosis. Knockdown of LGR5 attenuated downstream TGFb signaling and increased cell proliferation, survival, and metastasis in an orthotopic model of colon cancer in vivo. Upon RSPO1 stimulation, LGR5 formed complexes with TGFb receptors. Studies of patient specimens indicate that LGR5 expression was reduced in advanced stages and positively correlated with markers of TGFb activation in colon cancer. Our study uncovers a novel cross-talk between LGR5 and TGFβ signaling in colon cancer and identifies LGR5 as a new modulator of TGFβ signaling able to suppress colon cancer metastasis.

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SN - 0008-5472

VL - 77

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JO - Cancer Research

JF - Cancer Research

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ER -

R-Spondin1/LGR5 activates TGFβ signaling and suppresses colon cancer metastasis

Abstract

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