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• W3002782139 abstract "•Periostin deficiency inhibits colorectal tumor formation in mice•Periostin is mainly secreted by fibroblasts to promote tumor cell proliferation•Periostin promotes YAP/TAZ nuclear localization and IL-6 expression in tumor cells•IL-6 promotes fibroblast activation and periostin expression during tumorigenesis Periostin is a multifunctional extracellular matrix protein involved in various inflammatory diseases and tumor metastasis; however, evidence regarding whether and how periostin actively contributes to inflammation-associated tumorigenesis remains elusive. Here, we demonstrate that periostin deficiency significantly inhibits the occurrence of colorectal cancer in azoxymethane/dextran sulfate sodium-treated mice and in ApcMin/+ mice. Moreover, periostin deficiency attenuates the severity of colitis and reduces the proliferation of tumor cells. Mechanistically, stromal fibroblast-derived periostin activates FAK-Src kinases through integrin-mediated outside-in signaling, which results in the activation of YAP/TAZ and, subsequently, IL-6 expression in tumor cells. Conversely, IL-6 induces periostin expression in fibroblasts by activating STAT3, which ultimately facilitates colorectal tumor development. These findings provide the evidence that periostin promotes colorectal tumorigenesis, and identify periostin- and IL-6-mediated tumor-stroma interaction as a promising target for treating colitis-associated colorectal cancer. Periostin is a multifunctional extracellular matrix protein involved in various inflammatory diseases and tumor metastasis; however, evidence regarding whether and how periostin actively contributes to inflammation-associated tumorigenesis remains elusive. Here, we demonstrate that periostin deficiency significantly inhibits the occurrence of colorectal cancer in azoxymethane/dextran sulfate sodium-treated mice and in ApcMin/+ mice. Moreover, periostin deficiency attenuates the severity of colitis and reduces the proliferation of tumor cells. Mechanistically, stromal fibroblast-derived periostin activates FAK-Src kinases through integrin-mediated outside-in signaling, which results in the activation of YAP/TAZ and, subsequently, IL-6 expression in tumor cells. Conversely, IL-6 induces periostin expression in fibroblasts by activating STAT3, which ultimately facilitates colorectal tumor development. These findings provide the evidence that periostin promotes colorectal tumorigenesis, and identify periostin- and IL-6-mediated tumor-stroma interaction as a promising target for treating colitis-associated colorectal cancer. Colorectal cancer (CRC) is one of the most common malignant tumors, with a high incidence and mortality. Previous studies have demonstrated that genetic mutation of adenomatous polyposis coli (APC) is closely associated with colorectal tumorigenesis (Moser et al., 1990Moser A.R. Pitot H.C. Dove W.F. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse.Science. 1990; 247: 322-324Crossref PubMed Scopus (1309) Google Scholar, Rakoff-Nahoum and Medzhitov, 2007Rakoff-Nahoum S. Medzhitov R. Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88.Science. 2007; 317: 124-127Crossref PubMed Scopus (484) Google Scholar, Karki et al., 2016Karki R. Man S.M. Malireddi R.K.S. Kesavardhana S. Zhu Q. Burton A.R. Sharma B.R. Qi X. Pelletier S. Vogel P. et al.NLRC3 is an inhibitory sensor of PI3K-mTOR pathways in cancer.Nature. 2016; 540: 583-587Crossref Scopus (126) Google Scholar). Chronic inflammation is another recognized driver of CRC (Grivennikov et al., 2010Grivennikov S.I. Greten F.R. Karin M. Immunity, inflammation, and cancer.Cell. 2010; 140: 883-899Abstract Full Text Full Text PDF PubMed Scopus (7427) Google Scholar, Huber et al., 2012Huber S. Gagliani N. Zenewicz L.A. Huber F.J. Bosurgi L. Hu B. Hedl M. Zhang W. O’Connor Jr., W. Murphy A.J. et al.IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine.Nature. 2012; 491: 259-263Crossref PubMed Scopus (542) Google Scholar). Current evidence has revealed that the interactions between tumor cells and their adjacent stromal cells play a critical role in colorectal tumorigenesis (Koliaraki et al., 2012Koliaraki V. Roulis M. Kollias G. Tpl2 regulates intestinal myofibroblast HGF release to suppress colitis-associated tumorigenesis.J. Clin. Invest. 2012; 122: 4231-4242Crossref PubMed Scopus (58) Google Scholar). However, it is still unclear how the resident stromal cells are activated by their adjacent tumor cells under the inflammatory condition, and how stromal cell-derived cytokines and extracellular matrix (ECM) proteins educate tumor cells in the pathogenesis of CRC. Periostin (encoded by Postn) was originally identified as an adhesion protein in mouse osteoblastic cells (Takeshita et al., 1993Takeshita S. Kikuno R. Tezuka K. Amann E. Osteoblast-specific factor 2: cloning of a putative bone adhesion protein with homology with the insect protein fasciclin I.Biochem. J. 1993; 294: 271-278Crossref PubMed Scopus (543) Google Scholar, Horiuchi et al., 1999Horiuchi K. Amizuka N. Takeshita S. Takamatsu H. Katsuura M. Ozawa H. Toyama Y. Bonewald L.F. Kudo A. Identification and characterization of a novel protein, periostin, with restricted expression to periosteum and periodontal ligament and increased expression by transforming growth factor beta.J. Bone Miner. Res. 1999; 14: 1239-1249Crossref PubMed Scopus (802) Google Scholar). Periostin is rarely detected in most normal adult tissues, but it is highly induced in lesions, inflammation, and tumors (Conway et al., 2014Conway S.J. Izuhara K. Kudo Y. Litvin J. Markwald R. Ouyang G. Arron J.R. Holweg C.T. Kudo A. The role of periostin in tissue remodeling across health and disease.Cell. Mol. Life Sci. 2014; 71: 1279-1288Crossref PubMed Scopus (269) Google Scholar, Liu et al., 2014Liu A.Y. Zheng H. Ouyang G. Periostin, a multifunctional matricellular protein in inflammatory and tumor microenvironments.Matrix Biol. 2014; 37: 150-156Crossref PubMed Scopus (133) Google Scholar, Izuhara et al., 2017Izuhara K. Nunomura S. Nanri Y. Ogawa M. Ono J. Mitamura Y. Yoshihara T. Periostin in inflammation and allergy.Cell. Mol. Life Sci. 2017; 74: 4293-4303Crossref PubMed Scopus (83) Google Scholar, Kudo, 2017Kudo A. Introductory review: periostin-gene and protein structure.Cell. Mol. Life Sci. 2017; 74: 4259-4268Crossref PubMed Scopus (45) Google Scholar, Ma et al., 2019Ma Z. Zhao X. Deng M. Huang Z. Wang J. Wu Y. Cui D. Liu Y. Liu R. Ouyang G. Bone marrow mesenchymal stromal cell-derived periostin promotes B-ALL progression by modulating CCL2 in leukemia cells.Cell Rep. 2019; 26: 1533-1543.e4Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar). As a multifunctional ECM protein, periostin contributes to tumor microenvironment remodeling during tumor progression. During breast tumor metastasis, cancer-associated fibroblast (CAF)-derived periostin is involved in the formation of the cancer stem cell niche, the perivascular niche, and the premetastatic niche in the lung (Malanchi et al., 2011Malanchi I. Santamaria-Martínez A. Susanto E. Peng H. Lehr H.A. Delaloye J.F. Huelsken J. Interactions between cancer stem cells and their niche govern metastatic colonization.Nature. 2011; 481: 85-89Crossref PubMed Scopus (984) Google Scholar, Wang and Ouyang, 2012Wang Z. Ouyang G. Periostin: a bridge between cancer stem cells and their metastatic niche.Cell Stem Cell. 2012; 10: 111-112Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, Ghajar et al., 2013Ghajar C.M. Peinado H. Mori H. Matei I.R. Evason K.J. Brazier H. Almeida D. Koller A. Hajjar K.A. Stainier D.Y. et al.The perivascular niche regulates breast tumour dormancy.Nat. Cell Biol. 2013; 15: 807-817Crossref PubMed Scopus (749) Google Scholar, Wang et al., 2016bWang Z. Xiong S. Mao Y. Chen M. Ma X. Zhou X. Ma Z. Liu F. Huang Z. Luo Q. Ouyang G. Periostin promotes immunosuppressive premetastatic niche formation to facilitate breast tumour metastasis.J. Pathol. 2016; 239: 484-495Crossref PubMed Scopus (67) Google Scholar). Activated hepatic stellate cell-derived periostin promotes the formation of a fibrotic microenvironment to facilitate the liver metastatic outgrowth of pancreatic cancer cells (Nielsen et al., 2016Nielsen S.R. Quaranta V. Linford A. Emeagi P. Rainer C. Santos A. Ireland L. Sakai T. Sakai K. Kim Y.S. et al.Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis.Nat. Cell Biol. 2016; 18: 549-560Crossref PubMed Scopus (250) Google Scholar). Our previous study demonstrated that periostin promotes the metastatic outgrowth of colon tumors in the liver by enhancing cell survival and angiogenesis (Bao et al., 2004Bao S. Ouyang G. Bai X. Huang Z. Ma C. Liu M. Shao R. Anderson R.M. Rich J.N. Wang X.F. Periostin potently promotes metastatic growth of colon cancer by augmenting cell survival via the Akt/PKB pathway.Cancer Cell. 2004; 5: 329-339Abstract Full Text Full Text PDF PubMed Scopus (468) Google Scholar). However, it remains largely unclear whether and how periostin is involved in colorectal tumorigenesis, especially in the development of colitis-associated CRC (CAC). Here, we demonstrate that periostin deficiency suppresses intestinal tumorigenesis in azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice and ApcMin/+ mice. We further observe that the deletion of periostin significantly reduces the proliferative cells and decreases nuclear YAP/TAZ in colorectal tumors in mice. Our results unveil that CAF-derived periostin promotes colorectal tumorigenesis through integrin-focal adhesion kinase (FAK)-Src signaling-mediated YAP/TAZ activation. To determine the impact of periostin on colorectal tumorigenesis, we used AOM/DSS to induce CAC in mice. To this end, mice received a single injection of AOM followed by three cycles of DSS administration (Figure S1A). During the course of AOM/DSS treatment, periostin knockout (Postn−/−) mice exhibited a significant reduction in body weight loss in comparison to wild-type (WT) mice (Figure 1A). During the first cycle of DSS treatment, the disease activity index was significantly decreased in Postn−/− mice compared to WT mice (Figure S1B). Histologically, AOM/DSS-administrated Postn−/− mice displayed clearly attenuated inflammation severity (Figure 1B). Moreover, the histopathological score was greatly reduced in the distal colon of Postn−/− mice compared to that of WT mice (Figure 1C). The enhanced colitis is invariably accompanied by more infiltrated inflammatory cells in the lamina propria. To further investigate whether periostin has an effect on immune cell infiltration under inflammatory conditions, we performed immunohistochemical assays to analyze the dense infiltration of inflammatory cells in the distal colon of WT and Postn−/− mice during the early and late stages of AOM/DSS administration. We found fewer infiltrated inflammatory cells in the colon tissues of Postn−/− mice than in those of WT controls (Figures 1D and 1E), suggesting that the deletion of periostin retards inflammatory cell infiltration in the distal colon of AOM/DSS-treated mice. At the end point of the experimental protocol, the colons of both WT and Postn−/− mice were collected and tumors were analyzed. Tumor incidence in WT mice was 100%, whereas <80% of Postn−/− mice formed tumors or polyps in the distal colon. In particular, a significant decrease in tumor numbers and a remarkable reduction in tumor size were observed in the colons of Postn−/− mice compared to WT mice (Figures 1F–1I, S1C, and S1D). The average tumor number per colon in Postn−/− mice (2.5 ± 0.4) was less than in WT mice (5.0 ± 0.4) (Figure 1F). Moreover, Postn−/− mice showed a significant reduction in the average tumor size compared with WT controls (Figure 1H). Although there was no significant difference in the number of small tumors (≤1 mm diameter) between WT and Postn−/− mice, 53.1% of tumors in WT mice developed into large tumors (>2 mm diameter), while only 37.5% of tumors in Postn−/− mice developed into large tumors (Figure 1I). The number of proliferative cells was dramatically decreased in the tumors of Postn−/− mice compared to those in WT tumors (Figures 1J–1L). Furthermore, the mRNA levels of many inflammation-associated cytokines such as interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and IL-1β were significantly reduced in the distal colonic tissues of Postn−/− mice compared with those of WT mice after AOM/DSS treatment (Figures 1M, S1E, and S1F). We also found that the protein levels of IL-6, TNF-α, and IL-1β were markedly decreased in the distal colonic tissues of Postn−/− mice (Figure 1N). Consistent with these results, we observed greatly decreased levels of inducible nitric oxide synthase (iNOS), extracellular signal-regulated kinase 1/2 (ERK1/2), and signal transducer and activator of transcription 3 (STAT3) phosphorylation in the colon tissue of Postn−/− mice compared with WT mice at day 80 of AOM/DSS treatment (Figure S1G), indicating that the absence of periostin prevents the activation of inflammatory signaling pathways in mice. These findings suggest that periostin deficiency inhibits colitis-associated colorectal carcinogenesis. To further investigate whether periostin promotes colorectal tumorigenesis in a spontaneous mouse intestinal tumor model, we used ApcMin/+ mice and Postn+/− mice to generate Postn+/+ApcMin/+ mice and Postn−/−ApcMin/+mice. After 6 months, tumors in the whole intestinal tract were detected. We found that Postn−/−ApcMin/+ mice had a lower tumor burden than Postn+/+ApcMin/+ mice both in the small and large intestines (Figures S2A–S2E). In addition, fewer Ki67+ cells were observed in the small and large intestines of Postn−/−ApcMin/+ mice compared with Postn+/+ApcMin/+ mice (Figures S2F and S2G). These findings were similar to the observation obtained from the AOM/DSS-induced CAC model, suggesting that the absence of periostin significantly suppresses intestinal tumorigenesis in different mouse models of colorectal tumors. As periostin has a critical role during the early phases of the inflammation (Figures 1A–1E, 1M, 1N, and S1B), we reasoned that pathological change differences between WT and Postn−/− mice may exist during early stages of the CAC progression. To this end, we examined the expression of periostin in the inflamed colonic tissue sections of WT mice treated with AOM/DSS for 15 days. Immunohistochemical staining showed that a higher level of periostin was deposited in the inflamed colon tissues compared to the normal colon tissues (Figure S3A). As shown in Figures S3B and S3C, a significant decrease in the incidence of dysplasia in Postn−/− mice was observed compared with that in WT mice. In contrast, the number of goblet cells in the colon of Postn−/− mice was greater than that in WT mice (Figures S3D and S3E), indicating that genetic ablation of periostin may protect secretory epithelial cells from damage under the inflammatory disorder. Furthermore, Postn−/− mice had fewer proliferative cells in the distal colon sections than WT mice after the first cycle of AOM/DSS administration (Figures S3F–S3I). Epithelial barrier dysfunction is prominent in patients with inflammatory bowel disease and is always related to the severity of inflammation disorder in animals (Sharma et al., 2018Sharma D. Malik A. Guy C.S. Karki R. Vogel P. Kanneganti T.D. Pyrin inflammasome regulates tight junction integrity to restrict colitis and tumorigenesis.Gastroenterology. 2018; 154: 948-964.e8Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). After DSS administration, the epithelial barrier is permeable and tight junction is lost within 2 days (Huber et al., 2012Huber S. Gagliani N. Zenewicz L.A. Huber F.J. Bosurgi L. Hu B. Hedl M. Zhang W. O’Connor Jr., W. Murphy A.J. et al.IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine.Nature. 2012; 491: 259-263Crossref PubMed Scopus (542) Google Scholar). Thus, we further analyzed the effect of periostin deficiency on tight junctions during the early stage (on day 8) of AOM/DSS administration. We found that AOM/DSS-treated Postn−/− mice exhibited a significant increase in the expression of tight junction markers compared with AOM/DSS-treated WT mice (Figure S3J). In addition, even at this early time point, we observed significantly decreased production of inflammatory mediator markers and reduced levels of tumor surrogate markers in the distal colon lysates of Postn−/− mice compared with WT mice (Figures S3K and S3L). These results demonstrate that the absence of periostin prevents precancerous lesion formation in colon tissues during the early phase of CAC progression. Next, we determined the cellular source of periostin in colorectal tumors. We found that the level of periostin was low in normal colon tissues and its deposition closely surrounded the pericryptal fibroblasts (Figure 2A). By contrast, a highly elevated level of periostin was observed both in the AOM/DSS-induced mouse colorectal tumors and in the Apc mutation-related mouse tumors (Figures 2A and S4A). Immunohistochemical staining assays also revealed that periostin was deposited in tumor stromal cells but not in tumor cells (Figure 2A). Immunofluorescence co-staining assays further determined that α-smooth muscle actin-positive (α-SMA+) or vimentin+ stromal cells, but not epithelial-derived tumor cells, contributed to the production of periostin (Figures 2B–2D), indicating that periostin is mainly derived from tumor stromal fibroblasts. We also observed an extremely low amount of periostin deposition in surrounding macrophages in colitis-associated colorectal tumors (Figure S4B). To further determine what kinds of stromal cells, stromal fibroblasts, or bone marrow (BM)-derived macrophages were the dominant source of periostin in colorectal tumorigenesis, we performed BM transplantation assays to generate four groups of BM chimera mice: Postn−/− mice transplanted with BM from WT mice (WT BM > Postn−/−), WT mice transplanted with BM from Postn−/− mice (Postn−/− BM > WT), and the two control groups consisting of Postn−/− mice transplanted with BM from Postn−/− mice (Postn−/− BM > Postn−/−), and WT mice transplanted with BM from WT mice (WT BM > WT). Next, we administrated these four groups of BM chimera mice with AOM/DSS to induce colitis-associated tumor formation. Postn−/− mice receiving BM from WT or Postn−/− mice showed body weight loss at a significant reduction level, compared to WT mice receiving either BM from Postn−/− or WT mice (Figure 2E). During the early phases of tumor progression, the disease activity index was significantly lower in Postn−/− mice transplanted with BM from WT or Postn−/− mice than in WT mice transplanted with BM from WT or Postn−/− mice (Figure S4C). Moreover, compared with irradiated WT mice, Postn−/− mice receiving lethal irradiation exhibited significantly decreased histological scores in the distal colonic tissue sections after AOM/DSS treatment for 80 days (Figures 2F and 2G), as well as fewer infiltrated inflammatory cells in the irradiation-insensitive compartment of Postn−/− mice (Figures 2H and 2I). These data suggest that periostin-deficient mice transplanted with BM cells have weakened colitis disease severity after AOM/DSS colitis. Postn−/− mice receiving either WT or Postn−/− mice-derived BM cells developed significantly decreased tumor numbers and reduced tumor loads than WT mice receiving Postn−/− or WT mice-derived BM cells (Figures 2J, 2K, and S4D–S4F). However, we observed no significant difference in tumor numbers or tumor load between WT mice transplanted with either WT mice-derived BM cells or Postn−/− mice-derived BM cells, as well as between Postn−/− mice transplanted with either Postn−/− mice-derived BM cells or WT mice-derived BM cells (Figures 2J, 2K, and S4D–S4F). Thus, these results demonstrate that periostin is mainly derived from stromal fibroblasts during colorectal tumorigenesis. Given that our results (Figures 1J–1L, S2F, and S2G) demonstrated that periostin deficiency decreases proliferative cells in the tumors of AOM/DSS-treated mice and ApcMin/+ mice, we further detected the proliferation-promoting capacity of periostin in vitro. We treated the CRC cell line CMT93 with the conditioned medium (CM) of the primary CAFs isolated from colorectal tumors in WT and Postn−/− mice. We observed that there were fewer Ki67+ or BrdU+ cells in CMT93 cells treated with Postn−/− CAF CM than in WT CAF CM-treated cells (Figures 3A–3D). Moreover, recombinant mouse periostin protein (rmPeriostin)-treated CMT93 cells showed many more proliferative cells than control groups (Figures 3E–3H). MTT assays also showed that rmPeriostin-treated CMT93 cells had a higher proliferative capability than PBS-treated cells (Figure 3I). These data suggest that periostin promotes the proliferation of colorectal tumor cells in vitro. Next, we sought to explore the mechanisms by which periostin promotes cell proliferation and colorectal tumorigenesis. Previous studies demonstrate that the transcriptional cofactor YAP plays a critical role in regulating tissue regeneration and tumorigenesis in the intestine (Zhou et al., 2011Zhou D. Zhang Y. Wu H. Barry E. Yin Y. Lawrence E. Dawson D. Willis J.E. Markowitz S.D. Camargo F.D. Avruch J. Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance.Proc. Natl. Acad. Sci. USA. 2011; 108: E1312-E1320Crossref PubMed Scopus (354) Google Scholar, Cai et al., 2015Cai J. Maitra A. Anders R.A. Taketo M.M. Pan D. β-Catenin destruction complex-independent regulation of Hippo-YAP signaling by APC in intestinal tumorigenesis.Genes Dev. 2015; 29: 1493-1506Crossref PubMed Scopus (135) Google Scholar, Yui et al., 2018Yui S. Azzolin L. Maimets M. Pedersen M.T. Fordham R.P. Hansen S.L. Larsen H.L. Guiu J. Alves M.R.P. Rundsten C.F. et al.YAP/TAZ-dependent reprogramming of colonic epithelium links ECM remodeling to tissue regeneration.Cell Stem Cell. 2018; 22: 35-49.e7Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar). Periostin is a well-known extracellular player in tissue regeneration, inflammation, and tumor progression (Conway et al., 2014Conway S.J. Izuhara K. Kudo Y. Litvin J. Markwald R. Ouyang G. Arron J.R. Holweg C.T. Kudo A. The role of periostin in tissue remodeling across health and disease.Cell. Mol. Life Sci. 2014; 71: 1279-1288Crossref PubMed Scopus (269) Google Scholar, Liu et al., 2014Liu A.Y. Zheng H. Ouyang G. Periostin, a multifunctional matricellular protein in inflammatory and tumor microenvironments.Matrix Biol. 2014; 37: 150-156Crossref PubMed Scopus (133) Google Scholar). Thus, we determined whether periostin acts as an extracellular regulator of YAP signaling in colorectal tumor development. To this end, we determined the levels of YAP and TAZ in the colon tumor tissues of WT and Postn−/− mice. We found that both the protein and mRNA levels of YAP and TAZ were greatly decreased in the tumors of Postn−/− mice compared with WT mice (Figures 4A–4C). The deletion of periostin resulted in attenuated YAP/TAZ nuclear localization in the colorectal tumor cells (Figure 4B), indicating that periostin deficiency decreases YAP/TAZ activation during colorectal tumorigenesis. Activated YAP serves as a transcriptional co-factor of TEADs to induce their target gene expression. qRT-PCR analysis further revealed that the production of their target genes, such as Ankrd1, Ctgf, and Cyr61, was markedly reduced in the tumor lysates of Postn−/− mice relative to the production in WT tumor lysates (Figure 4C). To further determine whether periostin induces YAP/TAZ activation in colorectal tumor cells, we detected nuclear translocation of YAP/TAZ in CMT93 cells treated with WT and Postn−/− CAF CM, respectively. Notably, Postn−/− CAF-CM, but not WT CAF-CM, failed to enhance YAP/TAZ nuclear translocation in CMT93 cells (Figures 4D and 4E). These results were further confirmed by rmPeriostin-induced YAP/TAZ nuclear localization in CMT93 cells (Figures 4F and 4G). Moreover, rmPeriostin treatment strongly elevated the levels of YAP and TAZ in a time- and dose-dependent manner (Figures 4H and 4I). Administration of CMT93 cells with rmPeriostin showed a significant increase in the expression of YAP/TAZ target genes, but this effect was prevented by knocking down YAP/TAZ with short interfering RNAs (Figures 4J and S5A). These findings suggest that periostin enhances YAP/TAZ activation in colorectal tumor cells in vivo and in vitro. As a downstream effector of the Hippo signaling pathway, YAP can be directly phosphorylated by large tumor suppressor kinases 1 and 2 (LATS1/2) on several residues (Moroishi et al., 2015Moroishi T. Hansen C.G. Guan K.L. The emerging roles of YAP and TAZ in cancer.Nat. Rev. Cancer. 2015; 15: 73-79Crossref PubMed Scopus (790) Google Scholar, Gregorieff et al., 2015Gregorieff A. Liu Y. Inanlou M.R. Khomchuk Y. Wrana J.L. Yap-dependent reprogramming of Lgr5(+) stem cells drives intestinal regeneration and cancer.Nature. 2015; 526: 715-718Crossref PubMed Scopus (354) Google Scholar, Hong et al., 2016Hong A.W. Meng Z. Guan K.L. The Hippo pathway in intestinal regeneration and disease.Nat. Rev. Gastroenterol. Hepatol. 2016; 13: 324-337Crossref PubMed Scopus (162) Google Scholar). Phosphorylation of YAP at Ser127 is known to enhance YAP cytoplasmic localization and degradation by the proteasome (Guo et al., 2018Guo L. Cai T. Chen K. Wang R. Wang J. Cui C. Yuan J. Zhang K. Liu Z. Deng Y. et al.Kindlin-2 regulates mesenchymal stem cell differentiation through control of YAP1/TAZ.J. Cell Biol. 2018; 217: 1431-1451Crossref PubMed Scopus (57) Google Scholar). Phosphorylation-dependent nucleocytoplasmic shuttling of YAP is tightly associated with its activity (Zhao et al., 2010Zhao B. Li L. Tumaneng K. Wang C.Y. Guan K.L. A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP).Genes Dev. 2010; 24: 72-85Crossref PubMed Scopus (933) Google Scholar). We found that periostin significantly increased the abundance of YAP but reduced the phosphorylated level of YAP (Figures 4A, 4H, and 4I). Moreover, the treatment of rmPeriostin rescued the nuclear localization of YAP/TAZ in CMT93 cells grown even at high confluence (Figure S5B). To determine whether LATS1/2 were involved in regulating YAP phosphorylation and nuclear localization induced by periostin, we adopted short interfering RNAs to knock down LATS1/2 in CMT93 cells (Figure S5C) and treated them with rmPeriostin alone or in combination with RGD, an Arg-Gly-Asp motif peptide for binding and inhibiting integrin receptors. Notably, RGD treatment significantly prevented periostin-induced YAP/TAZ nuclear translocation, while LATS1/2 knockdown entirely reversed this effect, as evidenced by a highly increased percentage of YAP/TAZ nuclear localization (Figures 4K and S5D). In line with this, rmPeriostin treatment caused a significant reduction in LATS1 phosphorylation (Figure S5E). Furthermore, the forced decrease in YAP/TAZ expression in tumor cells markedly reduced tumor cell proliferation to a very low level, even in the presence of periostin stimulation (Figures 4L, S5F, and S5G). These results suggest that periostin promotes tumor cell proliferation and colorectal tumorigenesis through the activation of YAP/TAZ in a Hippo pathway-dependent manner. Next, we investigated the molecular mechanisms by which periostin induces YAP and TAZ activation in tumor cells. YAP can be directly phosphorylated and activated by active Src in intestine epithelial cells and breast cancer cells (Taniguchi et al., 2015Taniguchi K. Wu L.W. Grivennikov S.I. de Jong P.R. Lian I. Yu F.X. Wang K. Ho S.B. Boland B.S. Chang J.T. et al.A gp130-Src-YAP module links inflammation to epithelial regeneration.Nature. 2015; 519: 57-62Crossref PubMed Scopus (428) Google Scholar, Sorrentino et al., 2017Sorrentino G. Ruggeri N. Zannini A. Ingallina E. Bertolio R. Marotta C. Neri C. Cappuzzello E. Forcato M. Rosato A. et al.Glucocorticoid receptor signalling activates YAP in breast cancer.Nat. Commun. 2017; 8: 14073Crossref PubMed Scopus (101) Google Scholar). The current evidence demonstrates that periostin is one of the ligands and regulators of integrin/FAK signaling in tumor progression. In tumor microenvironments, the enhanced interaction of the ECM proteins, such as collagens, periostin, tenascin-C, and fibronectin, leads to integrin-mediated outside-in signaling, including FAK and Src activation. As an ECM component, periostin is highly expressed in the colorectal tumors and deposited in the matrix (Figures 2A–2D). Thus, we proposed that integrin-FAK-Src signaling may be involved in periostin-induced YAP activation in colorectal tumorigenesis. To test this hypothesis, we examined the protein levels of these signaling cascades in two different tumor cell lines by treatment with mouse or human recombinant periostin protein. We found that recombinant periostin treatment significantly elevated the levels of FAK and Src phosphorylation, as well as YAP, TAZ, and connective tissue growth factor (CTGF) in CMT93 and DLD1 tumor cells, which were significantly blocked by adding integrin inhibitory RGD peptide (Figures 5A–5C). We also found that periostin strongly enhanced AKT phosphorylation in the two different tumor cell lines (Figure 5A), which was in line with our previous work (Bao et al., 2004Bao S. Ouyang G. Bai X. Huang Z. Ma C. Liu M. Shao R. Anderson R.M. Rich J.N. Wang X.F. Periostin potently promotes metastatic growth of colon cancer by augmenting cell survival via the Akt/PKB pathway.Cancer Cell. 2004; 5: 329-339Abstract Full Text Full Text PDF PubMed Scopus (" @default.
• W3002782139 created "2020-01-30" @default.
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• W3002782139 date "2020-01-01" @default.
• W3002782139 modified "2023-10-14" @default.
• W3002782139 title "Periostin Promotes Colorectal Tumorigenesis through Integrin-FAK-Src Pathway-Mediated YAP/TAZ Activation" @default.
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