Suppression of pancreatic cancer liver metastasis by secretion-deficient ITIH5.
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
04
03
2020
accepted:
03
09
2020
revised:
14
08
2020
pubmed:
8
10
2020
medline:
21
4
2021
entrez:
7
10
2020
Statut:
ppublish
Résumé
Previously, we identified ITIH5 as a suppressor of pancreatic ductal adenocarcinoma (PDAC) metastasis in experimental models. Expression of ITIH5 correlated with decreased cell motility, invasion and metastasis without significant inhibition of primary tumour growth. Here, we tested whether secretion of ITIH5 is required to suppress liver metastasis and sought to understand the role of ITIH5 in human PDAC. We expressed mutant ITIH5 with deletion of the N-terminal secretion sequence (ITIH5Δs) in highly metastatic human PDAC cell lines. We used a human tissue microarray (TMA) to compare ITIH5 levels in uninvolved pancreas, primary and metastatic PDAC. Secretion-deficient ITIH5Δs was sufficient to suppress liver metastasis. Similar to secreted ITIH5, expression of ITIH5Δs was associated with rounded cell morphology, reduced cell motility and reduction of liver metastasis. Expression of ITIH5 is low in both human primary PDAC and matched metastases. Metastasis suppression by ITIH5 may be mediated by an intracellular mechanism. In human PDAC, loss of ITIH5 may be an early event and ITIH5-low PDAC cells in primary tumours may be selected for liver metastasis. Further defining the ITIH5-mediated pathway in PDAC could establish future therapeutic exploitation of this biology and reduce morbidity and mortality associated with PDAC metastasis.
Sections du résumé
BACKGROUND
Previously, we identified ITIH5 as a suppressor of pancreatic ductal adenocarcinoma (PDAC) metastasis in experimental models. Expression of ITIH5 correlated with decreased cell motility, invasion and metastasis without significant inhibition of primary tumour growth. Here, we tested whether secretion of ITIH5 is required to suppress liver metastasis and sought to understand the role of ITIH5 in human PDAC.
METHODS
We expressed mutant ITIH5 with deletion of the N-terminal secretion sequence (ITIH5Δs) in highly metastatic human PDAC cell lines. We used a human tissue microarray (TMA) to compare ITIH5 levels in uninvolved pancreas, primary and metastatic PDAC.
RESULTS
Secretion-deficient ITIH5Δs was sufficient to suppress liver metastasis. Similar to secreted ITIH5, expression of ITIH5Δs was associated with rounded cell morphology, reduced cell motility and reduction of liver metastasis. Expression of ITIH5 is low in both human primary PDAC and matched metastases.
CONCLUSIONS
Metastasis suppression by ITIH5 may be mediated by an intracellular mechanism. In human PDAC, loss of ITIH5 may be an early event and ITIH5-low PDAC cells in primary tumours may be selected for liver metastasis. Further defining the ITIH5-mediated pathway in PDAC could establish future therapeutic exploitation of this biology and reduce morbidity and mortality associated with PDAC metastasis.
Identifiants
pubmed: 33024269
doi: 10.1038/s41416-020-01093-z
pii: 10.1038/s41416-020-01093-z
pmc: PMC7782545
doi:
Substances chimiques
ITIH5 protein, human
0
Proteinase Inhibitory Proteins, Secretory
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
166-175Subventions
Organisme : NCI NIH HHS
ID : U54 CA163120
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM103418
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA036727
Pays : United States
Organisme : NCI NIH HHS
ID : F30 CA216998
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA127297
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211462
Pays : United States
Références
Siegel, R. L., Miller, K. D. & Jemal, A. Cancer Statistics, 2017. CA Cancer J. Clin. 67, 7–30 (2017).
doi: 10.3322/caac.21387
Sasaki K., Kurahara H., Young E. D., Natsugoe S., Ijichi A., Iwakuma T. et al. Genome-wide in vivo RNAi screen identifies ITIH5 as a metastasis suppressor in pancreatic cancer. Clin. Exp. Metastasis 34, 229–239 (2017).
Himmelfarb, M., Klopocki, E., Grube, S., Staub, E., Klaman, I., Hinzmann, B. et al. ITIH5, a novel member of the inter-alpha-trypsin inhibitor heavy chain family is downregulated in breast cancer. Cancer Lett. 204, 69–77 (2004).
doi: 10.1016/j.canlet.2003.09.011
Hamm, A., Veeck, J., Bektas, N., Wild, P. J. & Hartmann, A. Frequent expression loss of Inter-alpha-trypsin inhibitor heavy chain (ITIH) genes in multiple human solid tumors: a systematic expression analysis. BMC Cancer 8, 25 (2008).
doi: 10.1186/1471-2407-8-25
Pita, J. M., Banito, A., Cavaco, B. M. & Leite, V. Gene expression profiling associated with the progression to poorly differentiated thyroid carcinomas. Br. J. Cancer 101, 1782–1791 (2009).
doi: 10.1038/sj.bjc.6605340
Lu, Y., Liu, P., Wen, W., Grubbs, C. J., Townsend, R. R., Malone, J. P. et al. Cross-species comparison of orthologous gene expression in human bladder cancer and carcinogen-induced rodent models. Am. J. Transl. Res. 3, 8–27 (2010).
pubmed: 21139803
pmcid: 2981423
Oing, C., Jost, E., Dahl, E., Wilop, S., Brummendorf, T. H. & Galm, O. Aberrant DNA hypermethylation of the ITIH5 tumor suppressor gene in acute myeloid leukemia. Clin. Epigenetics 2, 419–423 (2011).
doi: 10.1007/s13148-011-0043-5
Zhang, S., Feng, X. L., Shi, L., Gong, C. J., He, Z. J., Wu, H. J. et al. Genome-wide analysis of DNA methylation in tongue squamous cell carcinoma. Oncol. Rep. 29, 1819–1826 (2013).
doi: 10.3892/or.2013.2309
Kloten, V., Rose, M., Kaspar, S., von Stillfried, S., Knuchel, R. & Dahl, E. Epigenetic inactivation of the novel candidate tumor suppressor gene ITIH5 in colon cancer predicts unfavorable overall survival in the CpG island methylator phenotype. Epigenetics 9, 1290–1301 (2014).
doi: 10.4161/epi.32089
Perez-Ramirez, M., Hernandez-Jimenez, A. J., Guerrero-Guerrero, A., Benadon-Darszon, E., Perezpena-Diazconti, M., Siordia-Reyes, A. G. et al. Genomics and epigenetics: A study of ependymomas in pediatric patients. Clin. Neurol. Neurosurg. 144, 53–58 (2016).
doi: 10.1016/j.clineuro.2016.02.041
Veeck, J., Chorovicer, M., Naami, A., Breuer, E., Zafrakas, M., Bektas, N. et al. The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation. Oncogene 27, 865–876 (2008).
doi: 10.1038/sj.onc.1210669
Rose, M., Bringezu, S., Godfrey, L., Fiedler, D., Gaisa, N. T., Koch, M. et al. ITIH5 and ECRG4 DNA methylation biomarker test (EI-BLA) for urine-based non-invasive detection of bladder cancer. Int. J. Mol. Sci. 21, 1117 (2020).
doi: 10.3390/ijms21031117
Rose, M., Meurer, S. K., Kloten, V., Weiskirchen, R., Denecke, B., Antonopoulos, W. et al. ITIH5 induces a shift in TGF-beta superfamily signaling involving Endoglin and reduces risk for breast cancer metastasis and tumor death. Mol. Carcinog. 57, 167–181 (2018).
doi: 10.1002/mc.22742
Rose, M., Kloten, V., Noetzel, E., Gola, L., Ehling, J., Heide, T. et al. ITIH5 mediates epigenetic reprogramming of breast cancer cells. Mol. Cancer 16, 44 (2017).
doi: 10.1186/s12943-017-0610-2
Zhuo, L. & Kimata, K. Structure and function of inter-alpha-trypsin inhibitor heavy chains. Connect Tissue Res. 49, 311–320 (2008).
doi: 10.1080/03008200802325458
Huang, L., Yoneda, M. & Kimata, K. A serum-derived hyaluronan-associated protein (SHAP) is the heavy chain of the inter alpha-trypsin inhibitor. J. Biol. Chem. 268, 26725–26730 (1993).
pubmed: 7504674
Zhao, M., Yoneda, M., Ohashi, Y., Kurono, S., Iwata, H., Ohnuki, Y. et al. Evidence for the covalent binding of SHAP, heavy chains of inter-alpha-trypsin inhibitor, to hyaluronan. J. Biol. Chem. 270, 26657–26663 (1995).
doi: 10.1074/jbc.270.44.26657
Green M. R., Sambrook J. & Sambrook J. Molecular Cloning: a Laboratory Manual, 4th ed. (Cold Spring Harbor Laboratory Press: Cold Spring Harbor, NY, 2012).
Schneider, C. A., Rasband, W. S. & Eliceiri, K. W. NIH Image to ImageJ: 25 years of image analysis. Nat. Methods 9, 671–675 (2012).
doi: 10.1038/nmeth.2089
Baecker V. ImageJ macro tool sets for biological image analysis. http://dev.mri.cnrs.fr/projects/imagej-macros/wiki/Wound_Healing_Tool . Accessed 12/12/2016, 2016 (2012).
Thery, C., Amigorena, S., Raposo, G. & Clayton, A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr. Protoc. Cell Biol. Chapter 3, Unit 3 22 (2006).
pubmed: 18228490
Kosugi, S., Hasebe, M., Entani, T., Takayama, S., Tomita, M. & Yanagawa, H. Design of peptide inhibitors for the importin alpha/beta nuclear import pathway by activity-based profiling. Chem. Biol. 15, 940–949 (2008).
doi: 10.1016/j.chembiol.2008.07.019
Kosugi, S., Hasebe, M., Tomita, M. & Yanagawa, H. Systematic identification of cell cycle-dependent yeast nucleocytoplasmic shuttling proteins by prediction of composite motifs. Proc. Natl Acad. Sci. USA 106, 10171–10176 (2009).
doi: 10.1073/pnas.0900604106
Kurahara, H., Bohl, C., Natsugoe, S., Nishizono, Y., Harihar, S., Sharma, R. et al. Suppression of pancreatic cancer growth and metastasis by HMP19 identified through genome-wide shRNA screen. Int. J. Cancer 139, 628–638 (2016).
doi: 10.1002/ijc.30110
R: A language and environment for statistical computing. (2015).
Linscheid C. R. Expression, Regulation and Release of Human Placental Antigens: Implications for the Maternal Immune Response to the Fetus [Dissertation]: (Anatomy and Cell Biology, University of Kansas, 2015)
Barretina, J., Caponigro, G., Stransky, N., Venkatesan, K., Margolin, A. A., Kim, S. et al. The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603–607 (2012).
doi: 10.1038/nature11003
Sanders, S. L., Whitfield, K. M., Vogel, J. P., Rose, M. D. & Schekman, R. W. Sec61p and BiP directly facilitate polypeptide translocation into the ER. Cell 69, 353–365 (1992).
doi: 10.1016/0092-8674(92)90415-9
Swiatly, A., Horala, A., Hajduk, J., Matysiak, J., Nowak-Markwitz, E. & Kokot, Z. J. MALDI-TOF-MS analysis in discovery and identification of serum proteomic patterns of ovarian cancer. BMC Cancer 17, 472 (2017).
doi: 10.1186/s12885-017-3467-2
Li, X., Li, B., Li, B., Guo, T., Sun, Z., Li, X. et al. ITIH4: effective serum marker, early warning and diagnosis, hepatocellular carcinoma. Pathol. Oncol. Res. 24, 663–670 (2018).
doi: 10.1007/s12253-017-0285-4
Bost, F., Diarra-Mehrpour, M. & Martin, J. P. Inter-alpha-trypsin inhibitor proteoglycan family-a group of proteins binding and stabilizing the extracellular matrix. Eur. J. Biochem. 252, 339–346 (1998).
doi: 10.1046/j.1432-1327.1998.2520339.x
Rapoport, T. A. Protein transport across the endoplasmic reticulum membrane: facts, models, mysteries. FASEB J. 5, 2792–2798 (1991).
doi: 10.1096/fasebj.5.13.1916103
Kanner, E. M., Friedlander, M. & Simon, S. M. Co-translational targeting and translocation of the amino terminus of opsin across the endoplasmic membrane requires GTP but not ATP. J. Biol. Chem. 278, 7920–7926 (2003).
doi: 10.1074/jbc.M207462200
Morcel, K., Watrin, T., Jaffre, F., Deschamps, S., Omilli, F., Pellerin, I. et al. Involvement of ITIH5, a candidate gene for congenital uterovaginal aplasia (Mayer-Rokitansky-Kuster-Hauser syndrome), in female genital tract development. Gene Expr. 15, 207–214 (2012).
doi: 10.3727/105221613X13571653093169
Zhong, Y., Macgregor-Das, A., Saunders, T., Whittle, M. C., Makohon-Moore, A., Kohutek, Z. A. et al. Mutant p53 together with TGFbeta signaling influence organ-specific hematogenous colonization patterns of pancreatic cancer. Clin. Cancer Res. 23, 1607–1620 (2017).
doi: 10.1158/1078-0432.CCR-15-1615