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IQGAP1 suppresses TβRII-mediated myofibroblastic activation and metastatic growth in liver
Chunsheng Liu, … , Vijay H. Shah, Ningling Kang
Chunsheng Liu, … , Vijay H. Shah, Ningling Kang
Published February 1, 2013
Citation Information: J Clin Invest. 2013;123(3):1138-1156. https://doi.org/10.1172/JCI63836.
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Research Article Oncology Article has an altmetric score of 27

IQGAP1 suppresses TβRII-mediated myofibroblastic activation and metastatic growth in liver

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Abstract

In the tumor microenvironment, TGF-β induces transdifferentiation of quiescent pericytes and related stromal cells into myofibroblasts that promote tumor growth and metastasis. The mechanisms governing myofibroblastic activation remain poorly understood, and its role in the tumor microenvironment has not been explored. Here, we demonstrate that IQ motif containing GTPase activating protein 1 (IQGAP1) binds to TGF-β receptor II (TβRII) and suppresses TβRII-mediated signaling in pericytes to prevent myofibroblastic differentiation in the tumor microenvironment. We found that TGF-β1 recruited IQGAP1 to TβRII in hepatic stellate cells (HSCs), the resident liver pericytes. Iqgap1 knockdown inhibited the targeting of the E3 ubiquitin ligase SMAD ubiquitination regulatory factor 1 (SMURF1) to the plasma membrane and TβRII ubiquitination and degradation. Thus, Iqgap1 knockdown stabilized TβRII and potentiated TGF-β1 transdifferentiation of pericytes into myofibroblasts in vitro. Iqgap1 deficiency in HSCs promoted myofibroblast activation, tumor implantation, and metastatic growth in mice via upregulation of paracrine signaling molecules. Additionally, we found that IQGAP1 expression was downregulated in myofibroblasts associated with human colorectal liver metastases. Taken together, our studies demonstrate that IQGAP1 in the tumor microenvironment suppresses TβRII and TGF-β dependent myofibroblastic differentiation to constrain tumor growth.

Authors

Chunsheng Liu, Daniel D. Billadeau, Haitham Abdelhakim, Edward Leof, Kozo Kaibuchi, Carmelo Bernabeu, George S. Bloom, Liu Yang, Lisa Boardman, Vijay H. Shah, Ningling Kang

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Figure 12

IQGAP1-knockdown HSCs promote the proliferation, migration, and survival of tumor cells.

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IQGAP1-knockdown HSCs promote the proliferation, migration, and survival...
(A) Conditioned medium collected from control and IQGAP1-knockdown HSCs were used as a growth stimulant for HT-29 in nonradioactive cell proliferation assays. Conditioned medium of IQGAP1-knockdown HSCs promoted the proliferation of HT-29 cells as compared with that of control shRNA–transduced HSCs. CM, conditioned medium. *P < 0.05 by ANOVA; n = 3 repeats with similar results. (B) Conditioned medium collected as described in A were used as a chemoattractant for HT-29 in Boyden chamber assays. Conditioned medium of IQGAP1-knockdown HSCs promoted HT-29 migration as compared with that of control shRNA–transduced HSCs. *P < 0.05 by ANOVA; n = 3 repeats with similar results. Scale bar: 100 μm. (C) MC38 cells were suspended in basal medium or conditioned medium as described in A and seeded onto polyhydroxyethylmethacrylate (poly-HEMA) precoated culture dishes. After cells were incubated for 24 hours with gentle shaking, anoikis was assessed by DAPI staining of unfixed cells (top) and WB for PARP cleavage (lower right). Conditioned medium of IQGAP1-knockdown HSCs protected MC38 cells from anoikis as compared with that of control HSCs. *P < 0.05 by ANOVA. n = 3 repeats. Scale bar: 50 μm. (D) Control and IQGAP1-knockdown HSCs were harvested for RNA extraction and SYBR green–based real-time RT-PCR for SDF-1/CXCL12 and HGF. The mRNA level of SDF-1/CXCL12 or HGF was significantly increased by IQGAP1 knockdown in HSCs. *P < 0.05 by t test; n = 3 independent experiments.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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