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R-Spondin1/LGR5 Activates Tgfb Signaling and Suppresses Colon

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R-Spondin1/LGR5 Activates Tgfb Signaling and Suppresses Colon Published OnlineFirst September 22, 2017; DOI: 10.1158/0008-5472.CAN-17-0219 Cancer Tumor and Stem Cell Biology Research R-Spondin1/LGR5 Activates TGFb Signaling and Suppresses Colon Cancer Metastasis Xiaolin Zhou1, Liying Geng1, Degeng Wang2, Haowei Yi1, Geoffrey Talmon3,and Jing Wang1,4,5 Abstract Leucine-rich repeat containing G-protein–coupled receptor an orthotopic model of colon cancer in vivo.UponRSPO1 5 (LGR5), an intestinal stem cell marker, is known to exhibit stimulation, LGR5 formed complexes with TGFb receptors. tumor suppressor activity in colon cancer, the mechanism of Studies of patient specimens indicate that LGR5 expression which is not understood. Here we show that R-spondin 1 was reduced in advanced stages and positively correlated with (RSPO1)/LGR5 directly activates TGFb signaling cooperatively markers of TGFb activation in colon cancer. Our study with TGFb type II receptor in colon cancer cells, enhancing uncovers a novel cross-talk between LGR5 and TGFb signaling TGFb-mediated growth inhibition and stress-induced apopto- in colon cancer and identifies LGR5 as a new modulator sis. Knockdown of LGR5 attenuated downstream TGFb signal- of TGFb signaling able to suppress colon cancer metastasis. ing and increased cell proliferation, survival, and metastasis in Cancer Res; 77(23); 6589–602. Ó2017 AACR. Introduction providing evidence that intestinal tumors arise from LGR5-pos- itive cells. However, ablation of LGR5-positive stem cells in the LGR5, a leucine-rich repeat-containing G-protein–coupled crypts had no effect on APC loss–induced crypt hyperplasia (12), receptor (GPCR; refs. 1, 2), was found to be a marker for prolif- indicating that the absence of LGR5 does not impair intestinal erating adult stem cells in small intestine (3). LGR5 and its tumor initiation. Furthermore, there are other conflicting reports homologs LGR4 and LGR6 are receptors of R-spondins (RSPO; regarding the functional role of LGR5 in colon cancer tumori- refs. 4, 5), which are secreted agonists of canonical Wnt signaling genesis. Some studies reported that RSPO/LGR5 signaling has a (6, 7). Unlike other GPCRs, LGR4-6 are not coupled to either G tumor suppressive activity in colon cancer (8, 13) whereas others proteins or b-arrestin after stimulation by RSPOs (4). Instead, they showed that LGR5 promotes tumorigenicity (14). Therefore, the have been shown to regulate Wnt canonical signaling, with both role of LGR5 in colon cancer tumorigenesis remains ambiguous, activation and inhibition reported in different cell contexts (5, 8). although in a transposon mutagenesis study RSPO2 scored sec- LGR5 itself is also a transcriptional target of Wnt signaling (9). ond only to APC as a colon cancer tumor suppressor locus (15). The physiological role of LGR5 during normal intestinal devel- Moreover, it is yet to be determined whether LGR5 contributes to opment and tumor initiation has been extensively studied. LGR5 colon cancer progression and metastasis. deficiency leads to premature Paneth cell differentiation, associ- TGFb regulates many aspects of cellular function. Upon ligand ated with Wnt activation, whereas it has no detectable effects on binding, TGFb type II receptor (RII) recruits and activates TGFb differentiation of other cell lineages, nor on epithelial cell pro- type I receptor (RI), which phosphorylates and activates Smad2/3. liferation or migration (10). The role of LGR5 in intestinal tumor Activated Smad2/3 form complexes with Smad4 and translocate development is controversial. Conditional deletion of APC in to the nucleus, where they regulate gene expression (16). The LGR5-positive but not LGR5-negative cells led to a rapid growth of TGFb axis has been shown to inhibit cell proliferation, induce large adenomas in small intestine in a mouse model (11), apoptosis, and suppress tumorigenicity in many colon cancer cell lines (17) and in intestinal adenomas (18). Abrogation of TGFb b 1Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela signaling increases metastasis whereas enhanced TGF signaling Buffett Cancer Center, Omaha, Nebraska. 2Department of Environmental Tox- suppresses metastasis in an orthotopic model of colon cancer icology, The Institute of Environmental and Human Health, Texas Tech Univer- (19, 20). In genetic mouse models, Smad3 or Smad4 mutation sity, Lubbock, Texas. 3Department of Pathology and Microbiology, University of increases malignancy and invasiveness of intestinal tumors of 4 þ Nebraska Medical Center, Nebraska Medical Center, Omaha, Nebraska. Depart- Apcmin/ or knockout mice (21, 22), indicating a suppressive role ment of Genetics, Cell Biology and Anatomy, Fred & Pamela Buffett Cancer 5 of TGFb signaling in malignant progression of colon tumors. Center, Omaha, Nebraska. Department of Biochemistry and Molecular Biology, b Fred & Pamela Buffett Cancer Center, Omaha, Nebraska. Indeed, TGF signaling is defective in 30% to 40% of colon cancer patients due to defects in TGFb RII or Smads (23, 24), and loss or Note: Supplementary data for this article are available at Cancer Research b Online (http://cancerres.aacrjournals.org/). reduction of TGF signaling is tightly associated with metastasis development (25, 26). X. Zhou and L. Geng contributed equally to the article. To address the potential function of LGR5 in colon cancer Corresponding Author: Jing Wang, University of Nebraska Medical Center, metastasis, we examined LGR5 expression in clinical specimens, 985950 Nebraska Medical Center, Omaha, NE 68198. Phone: 402-559-5558; Fax: and found that LGR5 expression decreased in advanced stages of 402-559-4651. E-mail: [email protected] colon cancer as compared to early stages. Knockdown of LGR5 doi: 10.1158/0008-5472.CAN-17-0219 expression in colon cancer cells increased their clonogenicity, Ó2017 American Association for Cancer Research. survival capacity in vitro, and liver and lung metastasis in an www.aacrjournals.org 6589 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst September 22, 2017; DOI: 10.1158/0008-5472.CAN-17-0219 Zhou et al. orthotopic model in vivo. Investigation of potential cross-talk vector. The retroviral expression vectors for C-terminal-tagged or between RSPO1/LGR5 and TGFb signaling revealed that non-tagged full-length human LGR5 were gifts from Dr. Keith RSPO1/LGR5 activated the canonical TGFb pathway and elicited Johnson (University of Nebraska Medical Center, Omaha, NE). its inhibitory effect on clonogenicity and cell survival of colon Dominant negative TCF expression vector (EdTC) was a gift from cancer cells through the activation of TGFb signaling. Mechanis- Roel Nusse (24310; Addgene). Transfection and infection were tically, LGR5 colocalized and formed complexes with TGFb performed as described previously (30). receptors upon RSPO1 stimulation. Importantly, LGR5 expres- sion positively correlated with Smad2 activation in colon cancer RT-PCR assays specimens. Therefore, our studies identify LGR5 as a novel com- Total RNA was isolated from colon cancer cells, liver, or lung of ponent/modulator of the TGFb signaling pathway and demon- mice using TRIzol reagent (15596026) from Thermo Fisher Sci- strate that RSPO1/LGR5 functions as a suppressor of colon cancer entific. Two micrograms of total RNA was reverse-transcribed to metastasis. cDNA with M-MLV reverse transcriptase (1701; Promega) using a random primer 2 mL of cDNA product was used to amplify specific Materials and Methods genes. Actin was used as a loading control. Sequences of primers Colon cancer cell culture for each gene were listed in Supplementary Table S1. Human colon carcinoma cell lines (HCT116, RKO, FET, CBS, HCT116b, and TENN) were originally established in Dr. Brattain's Colony formation and soft agarose assays lab in 1981 (27). All cell lines were validated by short-tandem For colony formation assays, cells were seeded in six-well plates repeat (STR) analyses at the University of Nebraska Medical at 500 cells per well. After 2 weeks, colonies were stained with MTT Center Human DNA Identification Laboratory. STR profiles were and dissolved in DMSO. Relative cell numbers were determined cross-checked with the ATCC database. HCT116 and RKO cell by OD values read at 570 nm. For soft agarose assays, cells were lines with 80% match with the ATCC online STR database are seeded in culture medium containing low melting point agar considered valid (28). STR profiles of FET, CBS, HCT116b, and (BMA50101; Lonza) at a density of 3,000 cells per well in 6-well TENN cell lines have never been reported before. Their STR plates. Colonies were stained with 1% iodonitrotetrazolium profiles were confirmed in ATCC database to be of human origin violet (I7375; Sigma-Aldrich) after 3 weeks and the numbers of and contain no mammalian interspecies contamination (Supple- colonies were counted. mentary Fig. S1A). There were 5–8 passages between thawing and use in the described experiments for all the cell lines. Apoptosis assays Cells were maintained at 37 C in a humidified incubator with Cells were plated and allowed to grow to 80% confluence 5% CO2 and cultured in McCoy's 5A serum-free medium (M4892; before switching to medium in the absence of growth factor or Sigma) supplemented with 10 ng/mL EGF, 20 mg/mL insulin, and serum supplements for 2–5 days. Apoptosis was determined by 4 mg/mL transferrin (29). When the cells were subjected to growth measuring cleaved PARP or cleaved caspase-9 or by performing factor deprivation stress, they
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