Abstract
Heat shock protein 47 (HSP47) is an important chaperone required for the correct folding and secretion of collagen. Several studies revealed that HSP47 has a role in numerous steps of collagen synthesis, preventing procollagen aggregation and inducing hydroxylation of proline and lysine residues. HSP47 is encoded by the SERPINH1 gene, which is located on chromosome 11q13.5, one of the most frequently amplified regions in human cancer. The altered expression levels of HSP47 have been correlated with several types of cancer, such as cervical, breast, pancreatic and gastric cancers. Studies have shown that HSP47 promotes tumor angiogenesis, growth, migration and metastatic capacity. In this review, we highlight the fundamental aspects of the interaction between HSP47 and collagen and the recent discoveries of the role of this chaperone in different types of malignant neoplasias. We also discuss recent treatments using HSP47 as a therapeutic target, and present evidences that HSP47 is an essential protein for cancer biology and a potential molecular target for chemotherapy.
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Alcantara MB, Nemazannikova N, Elahy M, Dass CR (2014) Pigment epithelium-derived factor upregulates collagen I and downregulates matrix metalloproteinase 2 in osteosarcoma cells, and colocalises to collagen i and heat shock protein 47 in fetal and adult bone. J Pharm Pharmacol 66:1586–1592. https://doi.org/10.1111/jphp.12289
Araki K, Mikami T, Yoshida T et al (2009) High expression of HSP47 in ulcerative colitis-associated carcinomas: proteomic approach. Br J Cancer 101:492–497. https://doi.org/10.1038/sj.bjc.6605163
Azuma M, Takeda Y, Nakajima H et al (2016) Biphasic function of TLR3 adjuvant on tumor and spleen dendritic cells promotes tumor T cell infiltration and regression in a vaccine therapy. Oncoimmunology 5:1–16. https://doi.org/10.1080/2162402X.2016.1188244
Blokzijl A, Ten Dijke P, Ibáez CF (2002) Physical and functional interaction between GATA-3 and SMAD3 allows TGF-β regulation of gata target genes. Curr Biol 12:35–45. https://doi.org/10.1016/S0960-9822(01)00623-6
Brandvold KR, Morimoto RI (2015) The chemical biology of molecular chaperones—implications for modulation of proteostasis. J Mol Biol 427:2931–2947. https://doi.org/10.1016/j.jmb.2015.05.010
Cao D, Maitra A, Saavedra J-A et al (2005) Expression of novel markers of pancreatic ductal adenocarcinoma in pancreatic nonductal neoplasms: additional evidence of different genetic pathways. Mod Pathol 18:752–761. https://doi.org/10.1038/modpathol.3800363
Chen Y, Terajima M, Yang Y et al (2015) Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma. J Clin Invest 125:1147–1162. https://doi.org/10.1172/JCI74725
Chou J, Lin JH, Brenot A et al (2013) GATA3 suppresses metastasis and modulates the tumour microenvironment by regulating microRNA-29b expression. Nat Cell Biol 15:201–213. https://doi.org/10.1038/ncb2672
Clarke EP, Jain N, Brickenden A et al (1993) Parallel regulation of procollagen-I and colligin, a collagen- binding protein and a member of the serine protease inhibitor family. JCell Biol 121:193–199. https://doi.org/10.1083/jcb.121.1.193
Curran CS, Keely PJ (2013) Breast tumor and stromal cell responses to TGF-β and hypoxia in matrix deposition. Matrix Biol 32:95–105. https://doi.org/10.1016/j.matbio.2012.11.016
Daniels CE, Jett JR (2005) Does interstitial lung disease predispose to lung cancer? Curr Opin Pulm Med 11:431–437. https://doi.org/10.1097/01.mcp.0000170521.71497.ba
Dufey E, Urra H, Hetz C (2015) ER proteostasis addiction in cancer biology: Novel concepts. Semin Cancer Biol 33:40–47. https://doi.org/10.1016/j.semcancer.2015.04.003
Duran I, Martin JH, Weis MA et al (2017) A chaperone complex formed by HSP47, FKBP65, and BiP modulates telopeptide lysyl hydroxylation of type I procollagen. J Bone Miner Res 32:1309–1319. https://doi.org/10.1002/jbmr.3095
Ek ETH, Dass CR, Contreras KG, Choong PFM (2007a) Pigment epithelium-derived factor overexpression inhibits orthotopic osteosarcoma growth, angiogenesis and metastasis. Cancer Gene Ther 14:616–626. https://doi.org/10.1038/sj.cgt.7701044
Ek ETH, Dass CR, Contreras KG, Choong PFM (2007b) Inhibition of orthotopic osteosarcoma growth and metastasis by multitargeted antitumor activities of pigment epithelium-derived factor. Clin Exp Metastasis 24:93–106. https://doi.org/10.1007/s10585-007-9062-1
Ferlay J, Soerjomataram I, Dikshit R et al (2015) Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136:E359–E386. https://doi.org/10.1002/ijc.29210
Fitchett CW, Hoffman GC (1986) Obstructing malignant lesions of the Colon. Surg Clin North Am 66:807–820. https://doi.org/10.1016/S0039-6109(16)43992-7
Ford AC, Moayyedi P, Hanauer SB (2013) Ulcerative colitis. BMJ 346:1–9. https://doi.org/10.1136/bmj.f432
Gelosa P, Sevin G, Pignieri A et al (2011) Terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, prevents hypertensive vascular hypertrophy and fibrosis. Am J Physiol Heart Circ Physiol 300:H762–H768. https://doi.org/10.1152/ajpheart.00880.2010
Hebert C, Norris K, Della Coletta R et al (1999) Cell surface colligin/Hsp47 associates with tetraspanin protein CD9 in epidermoid carcinoma cell lines. J Cell Biochem 73:248–258. https://doi.org/10.1002/(SICI)1097-4644(19990501)73:2%3C248::AID-JCB11%3E3.0.CO;2-A
Hebert C, Coletta RD, Norris K et al (2001) Non-natural CBP2 binding peptides and peptomers modulate carcinoma cell adhesion and invasion. J Cell Biochem 82:145–154. https://doi.org/10.1002/jcb.1146
Helleman J, Jansen MPHM, Ruigrok-Ritstier K et al (2008) Association of an extracellular matrix gene cluster with breast cancer prognosis and endocrine therapy response. Clin Cancer Res 14:5555–5564. https://doi.org/10.1158/1078-0432.CCR-08-0555
Hirai K, Kikuchi S, Kurita A et al (2006) Immunohistochemical Distribution of Heat Shock Protein 47 (HSP47) in Scirrhous Carcinoma of the Stomach. Anticancer Res 26:71–78
Hirayoshi K, Kudo H, Takechi H et al (1991) HSP47: a tissue-specific, transformation-sensitive, collagen-binding heat shock protein of chicken embryo fibroblasts. Mol Cell Biol 11:4036–4044. https://doi.org/10.1128/mcb.11.8.4036
Hosaka K, Yang Y, Seki T et al (2016) Pericyte–fibroblast transition promotes tumor growth and metastasis. Proc Natl Acad Sci 113:E5618–E5627. https://doi.org/10.1073/pnas.1608384113
Hosono J, Morikawa S, Ezaki T et al (2017) Pericytes promote abnormal tumor angiogenesis in a rat RG2 glioma model. Brain Tumor Pathol 34:120–129. https://doi.org/10.1007/s10014-017-0291-y
Huntoon CJ, Nye MD, Geng L et al (2010) Heat Shock Protein 90 (HSP90) inhibition depletes LATS1 and LATS2, two regulators of the mammalian Hippo tumor suppressor pathway. Cancer Res 70:8642–8650. https://doi.org/10.1158/0008-5472.CAN-10-1345
Ito S, Ogawa K, Takeuchi K et al (2017) A small-molecule compound inhibits a collagen-specific molecular chaperone and could represent a potential remedy for fibrosis. J Biol Chem 292:20076–20085. https://doi.org/10.1074/jbc.M117.815936
Jiang X, Zhou T, Wang Z et al (2016) HSP47 promotes glioblastoma stemlike cell survival by modulating tumor microenvironment extracellular matrix through TGF-β pathway. ACS Chem Neurosci 8:128–134. https://doi.org/10.1021/acschemneuro.6b00253
Kamikawaji K, Seki N, Watanabe M et al (2016) Regulation of LOXL2 and SERPINH1 by antitumor microRNA-29a in lung cancer with idiopathic pulmonary fibrosis. J Hum Genet 61:1–9. https://doi.org/10.1038/jhg.2016.99
Kimata Y, Kimata YI, Shimizu Y et al (2003) Genetic evidence for a role of BiP/Kar2 that regulates Ire1 in response to accumulation of unfolded proteins. Mol Biol Cell 14:2559–2569. https://doi.org/10.1091/mbc.E02
Kobayashi E, Satow R, Ono M et al (2014) MicroRNA expression and functional profiles of osteosarcoma. Oncol 86:94–103. https://doi.org/10.1159/000357408
Koide T, Takahara Y, Asada S, Nagata K (2002) Xaa-Arg-Gly triplets in the collagen triple helix are dominant binding sites for the molecular chaperone HSP47. J Biol Chem 277:6178–6182. https://doi.org/10.1074/jbc.M106497200
Kouros-Mehr H, Slorach EM, Sternlicht MD, Werb Z (2006) GATA-3 maintains the differentiation of the Luminal cell fate in the mammary gland. Cell 127:1041–1055. https://doi.org/10.1016/j.cell.2006.09.048
Layman DL, Ross R (1973) The production and secretion of procollagen peptidase by human fibroblasts in culture. Arch Biochem Biophys 157:451–456. https://doi.org/10.1016/0003-9861(73)90661-9
Li Y, Wang F, Xu J et al (2011) Progressive miRNA expression profiles in cervical carcinogenesis and identification of HPV-related target genes for miR-29. J Pathol 224:484–495. https://doi.org/10.1002/path.2873
Lindert U, Weis MA, Rai J et al (2015) Molecular consequences of the SERPINH1/HSP47 mutation in the dachshund natural model of osteogenesis imperfecta. J Biol Chem 290:17679–17689. https://doi.org/10.1074/jbc.M115.661025
Ma Y, Hendershot LM (2004) ER chaperone functions during normal and stress conditions. J Chem Neuroanat 28:51–65. https://doi.org/10.1016/j.jchemneu.2003.08.007
Maitra A, Iacobuzio-Donahue C, Rahman A et al (2002) Immunohistochemical validation of a novel epithelial and a novel stromal marker of pancreatic ductal adenocarcinoma identified by global expression microarrays: Sea urchin fascin homolog and heat shock protein 47. Am J Clin Pathol 118:52–59. https://doi.org/10.1309/3PAM-P5WL-2LV0-R4EG
Maloney A, Clarke PA, Naaby-Hansen S et al (2007) Gene and protein expression profiling of human ovarian cancer cells treated with the Heat Shock Protein 90 inhibitor 17-Allylamino-17-Demethoxygeldanamycin. Cancer Res 67:3239–3253. https://doi.org/10.1158/0008-5472.can-06-2968
Miyata S, Mizuno T, Koyama Y et al (2013) The endoplasmic reticulum-resident chaperone Heat Shock Protein 47 protects the Golgi apparatus from the effects of O-Glycosylation inhibition. PLoS One 8:1–20. https://doi.org/10.1371/journal.pone.0069732
Mori K, Toiyama Y, Otake K et al (2017) Proteomics analysis of differential protein expression identifies heat shock protein 47 as a predictive marker for lymph node metastasis in patients with colorectal cancer. Int J Cancer 140:1425–1435. https://doi.org/10.1002/ijc.30557
Nagata K, Yamada KM (1986) Phosphorylation and transformation sensitivity of a major collagen-binding protein of fibroblasts. J Biol Chem 261:7531–7536
Nagata K, Saga S, Yamada KM (1986) A major collagen-binding protein of chick embryo fibroblasts is a novel heat shock protein. J Cell Biol 103:223–229. https://doi.org/10.1083/jcb.103.1.223
Nakai A, Satoh M, Hirayoshi K, Nagata K (1992) Involvement of the stress protein HSP47 in procollagen processing in the endoplasmic reticulum. J Cell Biol 117:903–914. https://doi.org/10.1083/jcb.117.4.903
Nakayama S, Mukae H, Sakamoto N et al (2008) Pirfenidone inhibits the expression of HSP47 in TGF-β1-stimulated human lung fibroblasts. Life Sci 82:210–217. https://doi.org/10.1016/j.lfs.2007.11.003
Nan A, Ghandehari H, Hebert C et al (2005) Water-soluble polymers for targeted drug delivery to human squamous carcinoma of head and neck. J Drug Target 13:189–197. https://doi.org/10.1080/10611860500065187
Natsume T, Koide T, Yokota S et al (1994) Interactions between collagen-binding stress protein HSP47 and collagen: Analysis of kinetic parameters by surface plasmon resonance biosensor. J Biol Chem 269:31224–31228
Nishida N, Yano H, Nishida T et al (2006) Angiogenesis in cancer. Vasc Health Risk Manag 2:213–219. https://doi.org/10.2147/vhrm.2006.2.3.213
Polydorou C, Mpekris F, Papageorgis P et al (2017) Pirfenidone normalizes the tumor microenvironment to improve chemotherapy. Oncotarget 8:24506–24517. https://doi.org/10.18632/oncotarget.15534
Poschmann G, Sitek B, Sipos B et al (2009) Identification of proteomic differences between squamous cell carcinoma of the lung and bronchial epithelium. Mol Cell Proteomics 8:1105–1116. https://doi.org/10.1074/mcp.M800422-MCP200
Sasaki K, Yoshida H (2015) Organelle autoregulation—stress responses in the ER, Golgi, mitochondria and lysosome. J Biochem 157:185–195. https://doi.org/10.1093/jb/mvv010
Sato Y (2003) Molecular diagnosis of tumor angiogenesis and anti-angiogenic cancer therapy. Int J Clin Oncol 8:200–206. https://doi.org/10.1007/s10147-003-0342-8
Sauk JJ, Norris K, Hebert C et al (1998) Hsp47 binds to the KDEL receptor and cell surface expression is modulated by cytoplasmic and endosomal pH. Connect Tissue Res 37:105–119. https://doi.org/10.3109/03008209809028904
Sauk JJ, Coletta RD, Norris K, Hebert C (2000) Binding motifs of CBP2 a potential cell surface target for carcinoma cells. J Cell Biochem 78(20000801):251–263. https://doi.org/10.1002/(SICI)1097-4644(20000801)78:2%3C251::AID-JCB8%3E3.0.CO;2-G
Schedin P, Keely PJ (2011) Mammary gland ECM remodeling, stiffness, and mechanosignaling in normal development and tumor progression. Cold Spring Harb Perspect Biol 3:1–22. https://doi.org/10.1101/cshperspect.a003228
Schwab M (1998) Amplification of oncogenes in human cancer cells. BioEssays 20:473–479. https://doi.org/10.1002/(SICI)1521-1878(199806)20:6%3C473::AID-BIES5%3E3.0.CO;2-N
Sepulveda D, Rojas-Rivera D, Rodríguez DA et al (2018) Interactome screening identifies the ER luminal chaperone Hsp47 as a regulator of the unfolded protein response transducer IRE1α. Mol Cell 69:238–252. https://doi.org/10.1016/j.molcel.2017.12.028
Sharbeen G, McAlpine S, Phillips P (2015) HSP47: the new heat shock protein therapeutic target. In: McAlpine S, A. E (eds) Heat shock protein inhibitors, vol 19. Springer, Cham
Siller-Matula JM, Krumphuber J, Jilma B (2010) Pharmacokinetic, pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases: REVIEW. Br J Pharmacol 159:502–517. https://doi.org/10.1111/j.1476-5381.2009.00555.x
Suekane S, Ueda K, Nishihara K et al (2017) Personalized peptide vaccination as second-line treatment for metastatic upper tract urothelial carcinoma. Cancer Sci 108:2430–2437. https://doi.org/10.1111/cas.13404
Takechi H, Hirayoshi K, Nakai A et al (1992) Molecular cloning of a mouse 47-kDa heat-shock protein (HSP47), a collagen-binding stress protein, and its expression during the differentiation of F9 teratocarcinoma cells. Eur J Biochem 206:323–329. https://doi.org/10.1111/j.1432-1033.1992.tb16930.x
Tavassoli F, Deville P (eds) (2003) Pathology and genetics of tumours of the breast and female genital organs, 5th edn. IARC Press, Lyon
Thomson CA, Ananthanarayanan VS (2000) Structure–function studies on Hsp47: pH-dependent inhibition of collagen fibril formation in vitro. Biochem J 349:877–883. https://doi.org/10.1042/bj3490877
Thomson CA, Atkinson HM, Ananthanarayanan VS (2005) Identification of small molecule chemical inhibitors of the collagen-specific chaperone Hsp47. J Med Chem 48:1680–1684. https://doi.org/10.1021/jm049148&%23x002B;
Uozaki H, Ishida T, Kakiuchi C et al (2000) Expression of heat shock proteins in osteosarcoma and its relationship to prognosis. Pathol Res Pract 196:665–673. https://doi.org/10.1016/S0344-0338(00)80118-1
Verma V, Kim Y, Lee M-C et al (2016) Activated dendritic cells delivered in tissue compatible biomatrices induce in-situ anti-tumor CTL responses leading to tumor regression. Oncotarget 7:39894–39906. https://doi.org/10.18632/oncotarget.9529
Walker LC, Overstreet MA, Yeowell HN (2005) Tissue-specific expression and regulation of the alternatively-spliced forms of lysyl hydroxylase 2 (LH2) in human kidney cells and skin fibroblasts. Matrix Biol 23:515–523. https://doi.org/10.1016/j.matbio.2004.11.002
Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334:1081–1086. https://doi.org/10.1126/science.1209038
Wang SY (1994) A retinoic acid-inducible GATA-binding protein binds to the regulatory region of J6 serpin gene. J Biol Chem 269:607–613
Wang M, Kaufman RJ (2016) Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 529:326–335. https://doi.org/10.1038/nature17041
Wilson R, Lees JF, Bulleid NJ (1998) Protein disulfide isomerase acts as a molecular chaperone during the assembly of procollagen. J Biol Chem 273:9637–9643. https://doi.org/10.1074/jbc.273.16.9637
Wu ZB, Cai L, Qiu C et al (2014) CTL responses to HSP47 associated with the prolonged survival of patients with glioblastomas. Neurology 82:1261–1265. https://doi.org/10.1212/WNL.0000000000000290
Wu ZB, Cai L, Lin SJ et al (2016) Heat shock protein 47 promotes glioma angiogenesis. Brain Pathol 26:31–42. https://doi.org/10.1111/bpa.12256
Wu Q, Pi L, Le Trinh T et al (2017) A novel vaccine targeting Glypican-3 as a treatment for Hepatocellular carcinoma. Mol Ther 25:2299–2308. https://doi.org/10.1016/j.ymthe.2017.08.005
Xiang Q, Yang Y, Zhou Z et al (2012) Synthesis and in vitro anti-tumor activity of novel HPMA copolymer-drug conjugates with potential cell surface targeting property for carcinoma cells. Eur J Pharm Biopharm 80:379–386. https://doi.org/10.1016/j.ejpb.2011.10.020
Xu R, Mao J-H (2011) Gene transcriptional networks integrate microenvironmental signals in human breast cancer. Integr Biol 3:368–374. https://doi.org/10.1039/c0ib00087f
Xu CJ, Mikami T, Nakamura T et al (2013) Tumor budding, myofibroblast proliferation, and fibrosis in obstructing colon carcinoma: the roles of Hsp47 and basic fibroblast growth factor. Pathol Res Pract 209:69–74. https://doi.org/10.1016/j.prp.2012.10.008
Yamamoto N, Kinoshita T, Nohata N et al (2013) Tumor-suppressive microRNA-29a inhibits cancer cell migration and invasion via targeting HSP47 in cervical squamous cell carcinoma. Int J Oncol 43:1855–1863. https://doi.org/10.3892/ijo.2013.2145
Yamauchi M, Noyes C, Kuboki Y, Mechanic GL (1982) Collagen structural microheterogeneity and a possible role for glycosylated hydroxylysine in type I collagen. Proc Natl Acad Sci USA 79:7684–7688. https://doi.org/10.1073/pnas.79.24.7684
Zhang X, Yang J-J, Kim YS et al (2010) An 8-gene signature, including methylated and down-regulated glutathione peroxidase 3, of gastric cancer. Int J Oncol 36:405–414. https://doi.org/10.3892/ijo_00000513
Zhao D, Jiang X, Yao C et al (2014) Heat shock protein 47 regulated by miR-29a to enhance glioma tumor growth and invasion. J Neurooncol 118:39–47. https://doi.org/10.1007/s11060-014-1412-7
Zhao Y, Dang Z, Xu S, Chong S (2017) Heat shock protein 47 effects on hepatic stellate cell-associated receptors in hepatic fibrosis of Schistosoma japonicum-infected mice. Biol Chem 398:1357–1366. https://doi.org/10.1515/hsz-2017-0177
Zhu J, Xiong G, Fu H et al (2015) Chaperone Hsp47 drives malignant growth and invasion by modulating an ECM gene network. Cancer Res 75:1580–1591. https://doi.org/10.1158/0008-5472.CAN-14-1027
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Duarte, B.D.P., Bonatto, D. The heat shock protein 47 as a potential biomarker and a therapeutic agent in cancer research. J Cancer Res Clin Oncol 144, 2319–2328 (2018). https://doi.org/10.1007/s00432-018-2739-9
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DOI: https://doi.org/10.1007/s00432-018-2739-9