HCT-8 colon cancer cells secreted heat shock protein 90α (HSP90α) and had increased invasiveness upon serum starvation. The concentrated conditioned medium of serum-starved HCT-8 cells was able to stimulate the migration and invasion of non-serum-starved cells, which could be prevented by treatment with an anti-HSP90α antibody. Recombinant HSP90α (rHSP90α) also enhanced HCT-8 cell migration and invasion, suggesting a stimulatory role of secreted HSP90α in cancer malignancy. HSP90α binding to CD91α and Neu was evidenced by the proximity ligation assay, and rHSP90α-induced HCT-8 cell invasion could be suppressed by the addition of anti-CD91α or anti-Neu antibodies. Via CD91α and Neu, rHSP90α selectively induced integrin αV expression, and knockdown of integrin αV efficiently blocked rHSP90α-induced HCT-8 cell invasion. rHSP90α induced the activities of ERK, PI3K/Akt, and NF-κB p65, but only NF-κB activation was involved in HSP90α-induced integrin αV expression. Additionally, we investigated the serum levels of HSP90α and the expression status of tumor integrin αV mRNA in colorectal cancer patients. Serum HSP90α levels of colorectal cancer patients were significantly higher than those of normal volunteers (p < 0.001). Patients with higher serum HSP90α levels significantly exhibited elevated levels of integrin αV mRNA in tumor tissues as compared with adjacent non-tumor tissues (p < 0.001). Furthermore, tumor integrin αV overexpression was significantly correlated with TNM (Tumor, Node, Metastasis) staging (p = 0.001). HCT-8 colon cancer cells secreted heat shock protein 90α (HSP90α) and had increased invasiveness upon serum starvation. The concentrated conditioned medium of serum-starved HCT-8 cells was able to stimulate the migration and invasion of non-serum-starved cells, which could be prevented by treatment with an anti-HSP90α antibody. Recombinant HSP90α (rHSP90α) also enhanced HCT-8 cell migration and invasion, suggesting a stimulatory role of secreted HSP90α in cancer malignancy. HSP90α binding to CD91α and Neu was evidenced by the proximity ligation assay, and rHSP90α-induced HCT-8 cell invasion could be suppressed by the addition of anti-CD91α or anti-Neu antibodies. Via CD91α and Neu, rHSP90α selectively induced integrin αV expression, and knockdown of integrin αV efficiently blocked rHSP90α-induced HCT-8 cell invasion. rHSP90α induced the activities of ERK, PI3K/Akt, and NF-κB p65, but only NF-κB activation was involved in HSP90α-induced integrin αV expression. Additionally, we investigated the serum levels of HSP90α and the expression status of tumor integrin αV mRNA in colorectal cancer patients. Serum HSP90α levels of colorectal cancer patients were significantly higher than those of normal volunteers (p < 0.001). Patients with higher serum HSP90α levels significantly exhibited elevated levels of integrin αV mRNA in tumor tissues as compared with adjacent non-tumor tissues (p < 0.001). Furthermore, tumor integrin αV overexpression was significantly correlated with TNM (Tumor, Node, Metastasis) staging (p = 0.001). IntroductionHeat shock protein 90α (HSP90α) 2The abbreviations used are: HSP90αheat shock protein 90αrHSP90αrecombinant HSP90αPI3Kphosphatidylinositol 3-kinaseCRCcolorectal cancerCMconditioned mediumERKextracellular signal-regulated kinaseJNKc-Jun N-terminal kinaseMAPKmitogen-activated protein kinaseTNMtumor, node, metastasisFBSfetal bovine serumPBSphosphate-buffered salineELISAenzyme-linked immunosorbent assayRT-PCRreverse transcription-PCRshRNAshort hairpin RNA. is a molecular chaperone that aids in proper protein folding, maturation, and intracellular trafficking of numerous proteins (1Gething M.J. Sambrook J. Nature. 1992; 355: 33-45Crossref PubMed Scopus (3575) Google Scholar). Thus far, more than 100 proteins have been identified that are regulated by HSP90α, including Akt, Neu/Her-2 (ErbB2), HIF-1α, Bcr-Abl, Raf-1, and mutated p53 (2Tsutsumi S. Neckers L. Cancer Sci. 2007; 98: 1536-1539Crossref PubMed Scopus (200) Google Scholar). Many of these proteins are important mediators of signal transduction and cell cycle control and are also involved in the development and progression of cancer cells. Increasing evidence has suggested HSP90α as a novel therapeutic target. By inhibiting its chaperone activity, many HSP90α inhibitors cause the destabilization and eventual degradation of client proteins, and therefore, exhibit potent in vitro and in vivo anti-cancer activities (3Goetz M.P. Toft D.O. Ames M.M. Erlichman C. Ann. Oncol. 2003; 14: 1169-1176Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar). Among them, 17-allylamino-17-demethoxygeldanamycin is a first-in-class HSP90α inhibitor and is currently in phase II clinical trials. Nevertheless, most studies regarding HSP90α have focused on its function as a cytosolic chaperone; the secretion of HSP90α has been less well studied until recently.HSP90α is not only expressed in the cytoplasm, but it is also localized on the cell surface (4Sidera K. Samiotaki M. Yfanti E. Panayotou G. Patsavoudi E. J. Biol. Chem. 2004; 279: 45379-45388Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 5Becker B. Multhoff G. Farkas B. Wild P.J. Landthaler M. Stolz W. Vogt T. Exp. Dermatol. 2004; 13: 27-32Crossref PubMed Scopus (134) Google Scholar, 6Eustace B.K. Sakurai T. Stewart J.K. Yimlamai D. Unger C. Zehetmeier C. Lain B. Torella C. Henning S.W. Beste G. Scroggins B.T. Neckers L. Ilag L.L. Jay D.G. Nat. Cell Biol. 2004; 6: 507-514Crossref PubMed Scopus (477) Google Scholar). Through an interaction with the extracellular domain of Neu/Her-2, surface HSP90 is involved in heregulin-induced Neu/Her-2 activation and signaling, leading to cytoskeletal rearrangements and migration and invasion of breast cancer cells (7Sidera K. Gaitanou M. Stellas D. Matsas R. Patsavoudi E. J. Biol. Chem. 2008; 283: 2031-2041Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar). Recent studies have shown that HSP90 could be secreted by keratinocytes, non-small cell lung cancer CL1–5 cells, and breast cancer MCF-7 cells (8Hegmans J.P. Bard M.P. Hemmes A. Luider T.M. Kleijmeer M.J. Prins J.B. Zitvogel L. Burgers S.A. Hoogsteden H.C. Lambrecht B.N. Am. J. Pathol. 2004; 164: 1807-1815Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar, 9Li W. Li Y. Guan S. Fan J. Cheng C.F. Bright A.M. Chinn C. Chen M. Woodley D.T. EMBO J. 2007; 26: 1221-1233Crossref PubMed Scopus (217) Google Scholar, 10Xu A. Tian T. Hao J. Liu J. Zhang Z. Hao J. Wu S. Huang L. Xiao X. He D. J. Cancer Mol. 2007; 3: 107-112Google Scholar, 11Cheng C.F. Fan J. Fedesco M. Guan S. Li Y. Bandyopadhyay B. Bright A.M. Yerushalmi D. Liang M. Chen M. Han Y.P. Woodley D.T. Li W. Mol. Cell. Biol. 2008; 28: 3344-3358Crossref PubMed Scopus (162) Google Scholar, 12Wang X. Song X. Zhuo W. Fu Y. Shi H. Liang Y. Tong M. Chang G. Luo Y. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 21288-21293Crossref PubMed Scopus (190) Google Scholar). During skin wound healing, transforming growth factor-α induced keratinocytes to secrete HSP90α via an unconventional exosome pathway (9Li W. Li Y. Guan S. Fan J. Cheng C.F. Bright A.M. Chinn C. Chen M. Woodley D.T. EMBO J. 2007; 26: 1221-1233Crossref PubMed Scopus (217) Google Scholar, 11Cheng C.F. Fan J. Fedesco M. Guan S. Li Y. Bandyopadhyay B. Bright A.M. Yerushalmi D. Liang M. Chen M. Han Y.P. Woodley D.T. Li W. Mol. Cell. Biol. 2008; 28: 3344-3358Crossref PubMed Scopus (162) Google Scholar). Secreted HSP90α promoted both epidermal and dermal cell migration through their surface receptor CD91/LRP-1 (11Cheng C.F. Fan J. Fedesco M. Guan S. Li Y. Bandyopadhyay B. Bright A.M. Yerushalmi D. Liang M. Chen M. Han Y.P. Woodley D.T. Li W. Mol. Cell. Biol. 2008; 28: 3344-3358Crossref PubMed Scopus (162) Google Scholar). In a human cancer study, an elevated level of secreted HSP90α was detected from highly invasive CL1–5 cells as compared with their less invasive parental cells (10Xu A. Tian T. Hao J. Liu J. Zhang Z. Hao J. Wu S. Huang L. Xiao X. He D. J. Cancer Mol. 2007; 3: 107-112Google Scholar). Additionally, secretion of HSP90α was significantly induced from MCF-7 cells after stimulation with a variety of growth factors such as vascular endothelial growth factor, platelet-derived growth factor, and stromal cell-derived factor-1 (12Wang X. Song X. Zhuo W. Fu Y. Shi H. Liang Y. Tong M. Chang G. Luo Y. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 21288-21293Crossref PubMed Scopus (190) Google Scholar).In our present study, human colon cancer HCT-8 cells secreted HSP90α and increased cell invasiveness after serum starvation. Via CD91/LRP-1 and Neu, HSP90α selectively induced integrin αV expression, and shRNA-mediated knockdown of integrin αV efficiently blocked HSP90α-induced HCT-8 cell invasion. HSP90α induced activation of ERK, phosphatidylinositol 3-kinase (PI3K), and NF-κB p65 in HCT-8 cells, but only NF-κB activation was involved in HSP90α-induced integrin αV expression. In addition, we investigated the serum levels of HSP90α from 172 colorectal cancer (CRC) patients and the expression status of tumor integrin αV mRNA from 118 patients and analyzed their clinical relevance.DISCUSSIONHuman colon cancer HCT-8 cells secreted HSP90α and increased cell invasiveness in response to serum starvation stress. Our study further demonstrated that secreted HSP90α was an inducer of cancer cell migration and invasion. When a solid tumor grows beyond 2 mm in diameter, simple diffusion of nutrients and oxygen to metabolizing tissues is obviously insufficient so as that nutrient deficiency and hypoxia occur in multiple areas of tumor tissue. Many factors are produced within these areas to enhance angiogenesis or tumor cell spreading. Our data suggest that HSP90α could be one of these factors. Therefore, we analyzed serum levels of HSP90α from 10 normal volunteers and 172 CRC patients. Serum HSP90α levels of CRC patients were significantly higher than those of normal volunteers (p < 0.001). Furthermore, high stage (TNM III + IV) patients had higher HSP90α amounts in serum as compared with low stage (TNM I + II) patients, but the difference did not reach a statistically significant level. These results suggest that elevated HSP90α secretion occurs and affects CRC progression from earlier stages. Serum levels of HSP90α could potentially be used as an adjuvant diagnostic marker for colorectal neoplasia.HSP90 is a molecular chaperone that facilitates proper folding and intracellular trafficking of numerous client proteins (1Gething M.J. Sambrook J. Nature. 1992; 355: 33-45Crossref PubMed Scopus (3575) Google Scholar). Recent studies have shown that HSP90 is not only expressed in the cytoplasm and cell surface, but it can also be secreted by keratinocytes and cancer cells (8Hegmans J.P. Bard M.P. Hemmes A. Luider T.M. Kleijmeer M.J. Prins J.B. Zitvogel L. Burgers S.A. Hoogsteden H.C. Lambrecht B.N. Am. J. Pathol. 2004; 164: 1807-1815Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar, 9Li W. Li Y. Guan S. Fan J. Cheng C.F. Bright A.M. Chinn C. Chen M. Woodley D.T. EMBO J. 2007; 26: 1221-1233Crossref PubMed Scopus (217) Google Scholar, 10Xu A. Tian T. Hao J. Liu J. Zhang Z. Hao J. Wu S. Huang L. Xiao X. He D. J. Cancer Mol. 2007; 3: 107-112Google Scholar, 11Cheng C.F. Fan J. Fedesco M. Guan S. Li Y. Bandyopadhyay B. Bright A.M. Yerushalmi D. Liang M. Chen M. Han Y.P. Woodley D.T. Li W. Mol. Cell. Biol. 2008; 28: 3344-3358Crossref PubMed Scopus (162) Google Scholar, 12Wang X. Song X. Zhuo W. Fu Y. Shi H. Liang Y. Tong M. Chang G. Luo Y. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 21288-21293Crossref PubMed Scopus (190) Google Scholar). Because of the lack of N-terminal signaling sequence, its secretion has been thought to be via an unconventional manner. Some reports have revealed that HSP90α can be exported from cells by exocytosis via nano-vesicles at the plasma membrane called exosomes (8Hegmans J.P. Bard M.P. Hemmes A. Luider T.M. Kleijmeer M.J. Prins J.B. Zitvogel L. Burgers S.A. Hoogsteden H.C. Lambrecht B.N. Am. J. Pathol. 2004; 164: 1807-1815Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar, 14Clayton A. Turkes A. Navabi H. Mason M.D. Tabi Z. J. Cell Sci. 2005; 118: 3631-3638Crossref PubMed Scopus (343) Google Scholar, 15Lancaster G.I. Febbraio M.A. J. Biol. Chem. 2005; 280: 23349-23355Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar, 16Yu X. Harris S.L. Levine A.J. Cancer Res. 2006; 66: 4795-4801Crossref PubMed Scopus (514) Google Scholar). Additionally, phosphorylation of Thr-90 residue and interaction of the last four residues with protein phosphatase 5 have been thought to regulate HSP90α secretion (12Wang X. Song X. Zhuo W. Fu Y. Shi H. Liang Y. Tong M. Chang G. Luo Y. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 21288-21293Crossref PubMed Scopus (190) Google Scholar). The mechanism of HSP90α secretion after serum starvation remains to be investigated.It has been reported that cell surface HSP90α has a stimulatory role in cancer cell migration and invasion (2Tsutsumi S. Neckers L. Cancer Sci. 2007; 98: 1536-1539Crossref PubMed Scopus (200) Google Scholar), which is at least partly attributed to the interaction between HSP90α and Neu (7Sidera K. Gaitanou M. Stellas D. Matsas R. Patsavoudi E. J. Biol. Chem. 2008; 283: 2031-2041Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar). In our experiments, secreted or ectopic HSP90α enhanced HCT-8 cell migration and invasion via a physical interaction with cell surface CD91 rather than Neu, and the induced migration and invasion could be drastically abolished by treatment with anti-CD91 antibody. Indeed, CD91 has been known as a common receptor for HSP90, HSP70, GP96, and calreticulin (17Basu S. Binder R.J. Ramalingam T. Srivastava P.K. Immunity. 2001; 14: 303-313Abstract Full Text Full Text PDF PubMed Scopus (921) Google Scholar). The involvement of secreted HSP90α in cell migration and invasion through CD91 has also been demonstrated in skin cells during wound healing (9Li W. Li Y. Guan S. Fan J. Cheng C.F. Bright A.M. Chinn C. Chen M. Woodley D.T. EMBO J. 2007; 26: 1221-1233Crossref PubMed Scopus (217) Google Scholar, 11Cheng C.F. Fan J. Fedesco M. Guan S. Li Y. Bandyopadhyay B. Bright A.M. Yerushalmi D. Liang M. Chen M. Han Y.P. Woodley D.T. Li W. Mol. Cell. Biol. 2008; 28: 3344-3358Crossref PubMed Scopus (162) Google Scholar). In addition, the Toll-like receptor TLR-4 serves as a HSP90 receptor in antigen-presenting cells such as macrophages and dendritic cells in response to bacterial infection (18Triantafilou M. Triantafilou K. Biochem. Soc. Trans. 2004; 32: 636-639Crossref PubMed Scopus (127) Google Scholar), and annexin II is another cell surface HSP90α-binding protein in endothelial cells (19Lei H. Romeo G. Kazlauskas A. Circ. Res. 2004; 94: 902-909Crossref PubMed Scopus (52) Google Scholar). In our study, the anti-Neu antibody could prevent to some extent HCT-8 cell migration and invasion induced by secreted HSP90α, revealing that Neu participates in the function of secreted HSP90α. It remains to be studied whether TLR-4 and annexin II are also involved in HSP90α-induced cancer cell migration and invasion.CD91 is a cell membrane protein with multiple functions (13Lillis A.P. Van Duyn L.B. Murphy-Ullrich J.E. Strickland D.K. Physiol. Rev. 2008; 88: 887-918Crossref PubMed Scopus (504) Google Scholar). It is involved in cell endocytosis. It also functions as a receptor for α2-macroglobulin, transforming growth factor-β, and a variety of other ligands. CD91 has been shown to interact with many other cell membrane-associated proteins such as integrins. Integrins are a family of cell membrane receptors composed of non-covalently bound α and β subunits (20Hynes R.O. Cell. 2002; 110: 673-687Abstract Full Text Full Text PDF PubMed Scopus (6764) Google Scholar). Once bound by ligands or cellular counterreceptors, integrins gather many other proteins to form a focal adhesion complex. Some known signaling pathways and some undiscovered signaling pathways are thus triggered to regulate cell survival, proliferation, cell shape changes, adhesion, migration, and invasion. Our data have demonstrated that integrin αV expression was selectively induced by secreted HSP90α and that HSP90α-induced cell invasion could be drastically prevented by shRNA-mediated specific knockdown of integrin αV. The association of integrin αV with CRC malignancy was further confirmed by data from our clinical investigation, which demonstrated that tumor integrin αV mRNA overexpression was significantly correlated with the TNM staging of cancer patients. In the literature, integrin αV seems to be particularly important in angiogenesis (21Iivanainen E. Kähäri V.M. Heino J. Elenius K. Microsc. Res. Tech. 2003; 60: 13-22Crossref PubMed Scopus (84) Google Scholar). The integrin αVβ3 heterodimer was overexpressed in the vasculature of colon carcinomas and served as marker of tumor-associated blood vessels (22Max R. Gerritsen R.R. Nooijen P.T. Goodman S.L. Sutter A. Keilholz U. Ruiter D.J. De Waal R.M. Int. J. Cancer. 1997; 71: 320-324Crossref PubMed Scopus (169) Google Scholar). It is still unclear which β integrin can dimerize with αV to contribute to HSP90α-induced cancer cell invasion.Antibodies against CD91 and Neu exhibited different efficacies in preventing HSP90α-induced integrin αV expression, suggesting that CD91 and Neu were differentially involved in integrin αV induction. Additionally, we also investigated the signaling pathway responsible for HSP90α-induced integrin αV expression. Although rHSP90α induced the activities of ERK, PI3K/Akt, and NF-κB p65, rHSP90α-induced integrin αV expression was suppressed only by the inhibitor of NF-κB p65 activation. Taking these results together, we conclude that secreted HSP90α can stimulate HCT-8 cell invasion by inducing integrin αV expression via a CD91- and NF-κB-dependent pathway. Activation of the NF-κB pathway as a downstream event of CD91 has also been revealed in GP96-treated plasmacytoid dendritic cells (23De Filippo A. Binder R.J. Camisaschi C. Beretta V. Arienti F. Villa A. Della Mina P. Parmiani G. Rivoltini L. Castelli C. J. Immunol. 2008; 181: 6525-6535Crossref PubMed Scopus (23) Google Scholar). However, the detailed mechanism regarding NF-κB activation by CD91 still needs to be explored. IntroductionHeat shock protein 90α (HSP90α) 2The abbreviations used are: HSP90αheat shock protein 90αrHSP90αrecombinant HSP90αPI3Kphosphatidylinositol 3-kinaseCRCcolorectal cancerCMconditioned mediumERKextracellular signal-regulated kinaseJNKc-Jun N-terminal kinaseMAPKmitogen-activated protein kinaseTNMtumor, node, metastasisFBSfetal bovine serumPBSphosphate-buffered salineELISAenzyme-linked immunosorbent assayRT-PCRreverse transcription-PCRshRNAshort hairpin RNA. is a molecular chaperone that aids in proper protein folding, maturation, and intracellular trafficking of numerous proteins (1Gething M.J. Sambrook J. Nature. 1992; 355: 33-45Crossref PubMed Scopus (3575) Google Scholar). Thus far, more than 100 proteins have been identified that are regulated by HSP90α, including Akt, Neu/Her-2 (ErbB2), HIF-1α, Bcr-Abl, Raf-1, and mutated p53 (2Tsutsumi S. Neckers L. Cancer Sci. 2007; 98: 1536-1539Crossref PubMed Scopus (200) Google Scholar). Many of these proteins are important mediators of signal transduction and cell cycle control and are also involved in the development and progression of cancer cells. Increasing evidence has suggested HSP90α as a novel therapeutic target. By inhibiting its chaperone activity, many HSP90α inhibitors cause the destabilization and eventual degradation of client proteins, and therefore, exhibit potent in vitro and in vivo anti-cancer activities (3Goetz M.P. Toft D.O. Ames M.M. Erlichman C. Ann. Oncol. 2003; 14: 1169-1176Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar). Among them, 17-allylamino-17-demethoxygeldanamycin is a first-in-class HSP90α inhibitor and is currently in phase II clinical trials. Nevertheless, most studies regarding HSP90α have focused on its function as a cytosolic chaperone; the secretion of HSP90α has been less well studied until recently.HSP90α is not only expressed in the cytoplasm, but it is also localized on the cell surface (4Sidera K. Samiotaki M. Yfanti E. Panayotou G. Patsavoudi E. J. Biol. Chem. 2004; 279: 45379-45388Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 5Becker B. Multhoff G. Farkas B. Wild P.J. Landthaler M. Stolz W. Vogt T. Exp. Dermatol. 2004; 13: 27-32Crossref PubMed Scopus (134) Google Scholar, 6Eustace B.K. Sakurai T. Stewart J.K. Yimlamai D. Unger C. Zehetmeier C. Lain B. Torella C. Henning S.W. Beste G. Scroggins B.T. Neckers L. Ilag L.L. Jay D.G. Nat. Cell Biol. 2004; 6: 507-514Crossref PubMed Scopus (477) Google Scholar). Through an interaction with the extracellular domain of Neu/Her-2, surface HSP90 is involved in heregulin-induced Neu/Her-2 activation and signaling, leading to cytoskeletal rearrangements and migration and invasion of breast cancer cells (7Sidera K. Gaitanou M. Stellas D. Matsas R. Patsavoudi E. J. Biol. Chem. 2008; 283: 2031-2041Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar). Recent studies have shown that HSP90 could be secreted by keratinocytes, non-small cell lung cancer CL1–5 cells, and breast cancer MCF-7 cells (8Hegmans J.P. Bard M.P. Hemmes A. Luider T.M. Kleijmeer M.J. Prins J.B. Zitvogel L. Burgers S.A. Hoogsteden H.C. Lambrecht B.N. Am. J. Pathol. 2004; 164: 1807-1815Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar, 9Li W. Li Y. Guan S. Fan J. Cheng C.F. Bright A.M. Chinn C. Chen M. Woodley D.T. EMBO J. 2007; 26: 1221-1233Crossref PubMed Scopus (217) Google Scholar, 10Xu A. Tian T. Hao J. Liu J. Zhang Z. Hao J. Wu S. Huang L. Xiao X. He D. J. Cancer Mol. 2007; 3: 107-112Google Scholar, 11Cheng C.F. Fan J. Fedesco M. Guan S. Li Y. Bandyopadhyay B. Bright A.M. Yerushalmi D. Liang M. Chen M. Han Y.P. Woodley D.T. Li W. Mol. Cell. Biol. 2008; 28: 3344-3358Crossref PubMed Scopus (162) Google Scholar, 12Wang X. Song X. Zhuo W. Fu Y. Shi H. Liang Y. Tong M. Chang G. Luo Y. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 21288-21293Crossref PubMed Scopus (190) Google Scholar). During skin wound healing, transforming growth factor-α induced keratinocytes to secrete HSP90α via an unconventional exosome pathway (9Li W. Li Y. Guan S. Fan J. Cheng C.F. Bright A.M. Chinn C. Chen M. Woodley D.T. EMBO J. 2007; 26: 1221-1233Crossref PubMed Scopus (217) Google Scholar, 11Cheng C.F. Fan J. Fedesco M. Guan S. Li Y. Bandyopadhyay B. Bright A.M. Yerushalmi D. Liang M. Chen M. Han Y.P. Woodley D.T. Li W. Mol. Cell. Biol. 2008; 28: 3344-3358Crossref PubMed Scopus (162) Google Scholar). Secreted HSP90α promoted both epidermal and dermal cell migration through their surface receptor CD91/LRP-1 (11Cheng C.F. Fan J. Fedesco M. Guan S. Li Y. Bandyopadhyay B. Bright A.M. Yerushalmi D. Liang M. Chen M. Han Y.P. Woodley D.T. Li W. Mol. Cell. Biol. 2008; 28: 3344-3358Crossref PubMed Scopus (162) Google Scholar). In a human cancer study, an elevated level of secreted HSP90α was detected from highly invasive CL1–5 cells as compared with their less invasive parental cells (10Xu A. Tian T. Hao J. Liu J. Zhang Z. Hao J. Wu S. Huang L. Xiao X. He D. J. Cancer Mol. 2007; 3: 107-112Google Scholar). Additionally, secretion of HSP90α was significantly induced from MCF-7 cells after stimulation with a variety of growth factors such as vascular endothelial growth factor, platelet-derived growth factor, and stromal cell-derived factor-1 (12Wang X. Song X. Zhuo W. Fu Y. Shi H. Liang Y. Tong M. Chang G. Luo Y. Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 21288-21293Crossref PubMed Scopus (190) Google Scholar).In our present study, human colon cancer HCT-8 cells secreted HSP90α and increased cell invasiveness after serum starvation. Via CD91/LRP-1 and Neu, HSP90α selectively induced integrin αV expression, and shRNA-mediated knockdown of integrin αV efficiently blocked HSP90α-induced HCT-8 cell invasion. HSP90α induced activation of ERK, phosphatidylinositol 3-kinase (PI3K), and NF-κB p65 in HCT-8 cells, but only NF-κB activation was involved in HSP90α-induced integrin αV expression. In addition, we investigated the serum levels of HSP90α from 172 colorectal cancer (CRC) patients and the expression status of tumor integrin αV mRNA from 118 patients and analyzed their clinical relevance.
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