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IGFBP-rP1 suppresses epithelial-mesenchymal transition and metastasis in colorectal cancer.
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Cooperation of transforming growth factor-β (TGF-β) and other signaling pathways, such as Ras and Wnt, is essential to inducing EMT, but the molecular mechanisms remain to be fully determined.Here, we reported that insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1), a potential tumor suppressor, controls EMT in colorectal cancer progression.Moreover, we demonstrated that IGFBP-rP1 suppresses EMT and tumor metastasis by repressing TGF-β-mediated EMT through the Smad signaling cascade.
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PubMed Central - PubMed
Affiliation: 1] Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China [2] Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, Zhejiang, China.
ABSTRACT
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Epithelial-mesenchymal transition (EMT) was initially recognized during organogenesis and has recently been reported to be involved in promoting cancer invasion and metastasis. Cooperation of transforming growth factor-β (TGF-β) and other signaling pathways, such as Ras and Wnt, is essential to inducing EMT, but the molecular mechanisms remain to be fully determined. Here, we reported that insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1), a potential tumor suppressor, controls EMT in colorectal cancer progression. We revealed the inhibitory role of IGFBP-rP1 through analyses of clinical colorectal cancer samples and various EMT and metastasis models in vitro and in vivo. Moreover, we demonstrated that IGFBP-rP1 suppresses EMT and tumor metastasis by repressing TGF-β-mediated EMT through the Smad signaling cascade. These data establish that IGFBP-rP1 functions as a suppressor of EMT and metastasis in colorectal cancer. Related in: MedlinePlus |
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fig5: IGFBP-rP1 inhibits TGF-β receptor expression and its downstream signaling in SW620 and SW480 cells. (a) SW620 cell lysates from blk, vector, and IGFBP-rP1 cells were analyzed the indicated proteins by western blot. (b) SW480 cell lysates from scramble shRNA and IGFBP-rP1 shRNA cells were analyzed the indicated proteins by western blot. (c) Western blot of the indicated antibodies in two SW480-IGFBP-rP1 knockdown cell clones and controls untreated or treated with 10 ng/ml SB431542 for 48 h Mentions: TGF-β is considered as a very potent inducer of EMT and metastasis. Canonical Smad signaling, which is activated by TGF-β, has critical roles during the induction of EMT.22, 23 Previous microarray results revealed a relationship between IGFBP-rP1 and TGF-β signaling, especially Smad3. Therefore, we explored whether the effect of IGFBP-rP1 on EMT is mediated by TGF-β signaling. As expected, IGFBP-rP1 overexpression inactivated both TGF-β R I and R II in SW620 cells. Accordingly, phosphorylation of smad2 and smad3 was also decreased in the IGFBP-rP1 overexpressing cells as compared with the control cells (Figure 5a). In support of this, IGFBP-rP1 knockdown in SW480 cells increased the levels of TGF-β receptor and its main downstream effectors, phospho-Smad2/3 (Figure 5b). To further validate whether IGFBP-rP1 modulated the TGF-β/Smad signaling pathway, we used SB431542, which is a selective inhibitor of TGF-β/ALK5/Smad2 signaling. Western blots confirmed the inhibition of TGF-β R II and smad2/3 phosphorylation by SB431542 in two clones of IGFBP-rP1 knockdown SW480 cells. SB431542 rescued the EMT status induced by IGFBP-rP1 knockdown (Figure 5c). Overall, our data support that IGFBP-rP1 upregulates TGF-β receptor expression, with subsequent activation of TGF-β receptor pathways. |
View Article: PubMed Central - PubMed
Affiliation: 1] Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China [2] Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, Zhejiang, China.
