Mesothelin

Mesothelin
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 4F3F​
Identifiers
Symbols	MSLN ; MPF; SMRP
External IDs	OMIM: 601051 MGI: 1888992 HomoloGene: 4249 GeneCards: MSLN Gene
Gene ontology Molecular function • protein binding Cellular component • extracellular space • Golgi apparatus • plasma membrane • cell surface • membrane • anchored component of membrane Biological process • cell adhesion • pancreas development Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	10232	56047
Ensembl	ENSG00000102854	ENSMUSG00000063011
UniProt	Q13421	Q61468
RefSeq (mRNA)	NM_001177355	NM_018857
RefSeq (protein)	NP_001170826	NP_061345
Location (UCSC)	Chr 16: 0.64 – 0.77 Mb	Chr 17: 25.75 – 25.75 Mb
PubMed search

Mesothelin, also known as MSLN, is a protein that in humans is encoded by the MSLN gene.^[1][2]

Function

Mesothelin is a 40 kDa protein present on normal mesothelial cells and overexpressed in several human tumors, including mesothelioma and ovarian and pancreatic adenocarcinoma. The protein was first identified by its reactivity with monoclonal antibody K1.^[3] Subsequent cloning studies showed that the mesothelin gene encodes a precursor protein that is processed to yield mesothelin which is attached to the cell membrane by a glycophosphatidylinositol linkage and a 31-kDa shed fragment named megakaryocyte-potentiating factor (MPF). Although it has been proposed that mesothelin may be involved in cell adhesion, its biological function is not known.^[4]

Medical applications

Mesothelin is a tumour differentiation antigen that is normally present on the mesothelial cells lining the pleura, peritoneum and pericardium.^[5] Since mesothelin is overexpressed in several cancers and is immunogenic, the protein could be exploited as tumor marker or as the antigenic target of a therapeutic cancer vaccine.^[4][5]

Elevations of serum mesothelin specific to ovarian and other cancer patients may be measured using ELISA assays.^[6] Assays for blood-bourne mesothelin and MPF for tumor diagnosis, especially applied to asbestos-related mesothelioma have been developed.^[7] Elevated serum mesothelin was found in most patients with mesothelioma (71%) and ovarian cancer (67%).^[8] Blood MPF and mesothelin levels were correlated, with modest accuracy for malignant pleural mesothelioma and lung cancer (sensitivity 74% and 59%, specificity 90% and 86%, respectively for MPF and mesothelin assays).^[9] Circulating mesothelin is reported in nearly all pancreatic cancers,^[10] however the levels in healthy persons often exceed 80 ng/mL (using 40 kD molecular weight as the conversion factor) and to widely overlap the values in the pancreatic cancer patients.^[11] It was noted that the cutoff levels for normal could differ as much as 10-fold among publications, depending on the assay used (compare Sharon et al^[11] and Iwahori et al^[9] with Hassan et al^[8]) and thus that normal levels must be determined anew when new assays are introduced.

References

1. Kojima T, Oh-eda M, Hattori K, Taniguchi Y, Tamura M, Ochi N, Yamaguchi N (September 1995). "Molecular cloning and expression of megakaryocyte potentiating factor cDNA". J. Biol. Chem. 270 (37): 21984–90. doi:10.1074/jbc.270.37.21984. PMID 7665620.
2. Chang K, Pastan I (January 1996). "Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers". Proc. Natl. Acad. Sci. U.S.A. 93 (1): 136–40. doi:10.1073/pnas.93.1.136. PMC 40193. PMID 8552591.
3. Chang K, Pai LH, Batra JK, Pastan I, Willingham MC (January 1992). "Characterization of the Antigen (CAK1) Recognized by Monoclonal Antibody K1 Present on Ovarian Cancers and Normal Mesothelium". Cancer Res 52 (1): 181–6. PMID 1727378.
4. Hassan R, Bera T, Pastan I (June 2004). "Mesothelin: a new target for immunotherapy". Clin. Cancer Res. 10 (12 Pt 1): 3937–42. doi:10.1158/1078-0432.CCR-03-0801. PMID 15217923.
5. Hassan R, Ho M (January 2008). "Mesothelin targeted cancer immunotherapy". Eur. J. Cancer 44 (1): 46–53. doi:10.1016/j.ejca.2007.08.028. PMC 2265108. PMID 17945478.
6. Scholler N, Fu N, Yang Y, Ye Z, Goodman GE, Hellström KE, Hellström I (September 1999). "Soluble member(s) of the mesothelin/megakaryocyte potentiating factor family are detectable in sera from patients with ovarian carcinoma". Proc. Natl. Acad. Sci. U.S.A. 96 (20): 11531–6. Bibcode:1999PNAS...9611531S. doi:10.1073/pnas.96.20.11531. PMC 18068. PMID 10500211.
7. Maeda M, Hino O (2006). "Blood tests for asbestos-related mesothelioma". Oncology 71 (1–2): 26–31. doi:10.1159/000100446. PMID 17344668.
8. Hassan R, Remaley AT, Sampson ML, Zhang J, Cox DD, Pingpank J, Alexander R, Willingham M, Pastan I, Onda M (January 2006). "Detection and quantitation of serum mesothelin, a tumor marker for patients with mesothelioma and ovarian cancer". Clin. Cancer Res. 12 (2): 447–53. doi:10.1158/1078-0432.CCR-05-1477. PMID 16428485.
9. Iwahori K, Osaki T, Serada S, Fujimoto M, Suzuki H, Kishi Y, Yokoyama A, Hamada H, Fujii Y, Yamaguchi K, Hirashima T, Matsui K, Tachibana I, Nakamura Y, Kawase I, Naka T (October 2008). "Megakaryocyte potentiating factor as a tumor marker of malignant pleural mesothelioma: evaluation in comparison with mesothelin". Lung Cancer 62 (1): 45–54. doi:10.1016/j.lungcan.2008.02.012. PMID 18394747.
10. Johnston FM, Tan MC, Tan BR, Porembka MR, Brunt EM, Linehan DC, Simon PO, Plambeck-Suess S, Eberlein TJ, Hellstrom KE, Hellstrom I, Hawkins WG, Goedegebuure P (November 2009). "Circulating mesothelin protein and cellular antimesothelin immunity in patients with pancreatic cancer". Clin. Cancer Res. 15 (21): 6511–8. doi:10.1158/1078-0432.CCR-09-0565. PMC 2782601. PMID 19843662.
11. Sharon E, Zhang J, Hollevoet K, Steinberg SM, Pastan I, Onda M, Gaedcke J, Ghadimi BM, Ried T, Hassan R (April 2012). "Serum mesothelin and megakaryocyte potentiating factor in pancreatic and biliary cancers". Clin. Chem. Lab. Med. 50 (4): 721–5. doi:10.1515/CCLM.2011.816. PMID 22149739.

Further reading

• Alvarez H, Rojas PL, Yong KT, Ding H, Xu G, Prasad PN, Wang J, Canto M, Eshleman JR, Montgomery EA, Maitra A (December 2008). "Mesothelin is a specific biomarker of invasive cancer in the Barrett-associated adenocarcinoma progression model: translational implications for diagnosis and therapy". Nanomedicine 4 (4): 295–301. doi:10.1016/j.nano.2008.06.006. PMC 2606904. PMID 18691948.
• Cristaudo A, Foddis R, Bonotti A, Simonini S, Vivaldi A, Guglielmi G, Bruno R, Landi D, Gemignani F, Landi S (April 2010). "Polymorphisms in the putative micro-RNA-binding sites of mesothelin gene are associated with serum levels of mesothelin-related protein". Occup Environ Med 67 (4): 233–6. doi:10.1136/oem.2009.049205. PMID 19858537.
• Pu RT, Pang Y, Michael CW (January 2008). "Utility of WT-1, p63, MOC31, mesothelin, and cytokeratin (K903 and CK5/6) immunostains in differentiating adenocarcinoma, squamous cell carcinoma, and malignant mesothelioma in effusions". Diagn. Cytopathol. 36 (1): 20–5. doi:10.1002/dc.20747. PMID 18064689.
• Inami K, Kajino K, Abe M, Hagiwara Y, Maeda M, Suyama M, Watanabe S, Hino O (December 2008). "Secretion of N-ERC/mesothelin and expression of C-ERC/mesothelin in human pancreatic ductal carcinoma". Oncol. Rep. 20 (6): 1375–80. doi:10.3892/or_00000155. PMID 19020717.
• Roe OD, Creaney J, Lundgren S, Larsson E, Sandeck H, Boffetta P, Nilsen TI, Robinson B, Kjaerheim K (August 2008). "Mesothelin-related predictive and prognostic factors in malignant mesothelioma: a nested case-control study". Lung Cancer 61 (2): 235–43. doi:10.1016/j.lungcan.2007.12.025. PMID 18281122.
• Johnson MD, Vito F, O'Connell MJ (June 2008). "Mesothelin expression in the leptomeninges and meningiomas". J. Histochem. Cytochem. 56 (6): 579–85. doi:10.1369/jhc.2008.950477. PMC 2386771. PMID 18347077.
• Schneider J, Hoffmann H, Dienemann H, Herth FJ, Meister M, Muley T (November 2008). "Diagnostic and prognostic value of soluble mesothelin-related proteins in patients with malignant pleural mesothelioma in comparison with benign asbestosis and lung cancer". J Thorac Oncol 3 (11): 1317–24. doi:10.1097/JTO.0b013e318187491c. PMID 18978568.
• Pass HI, Wali A, Tang N, Ivanova A, Ivanov S, Harbut M, Carbone M, Allard J (January 2008). "Soluble mesothelin-related peptide level elevation in mesothelioma serum and pleural effusions". Ann. Thorac. Surg. 85 (1): 265–72; discussion 272. doi:10.1016/j.athoracsur.2007.07.042. PMID 18154821.
• Sapede C, Gauvrit A, Barbieux I, Padieu M, Cellerin L, Sagan C, Scherpereel A, Dabouis G, Grégoire M (March 2008). "Aberrant splicing and protease involvement in mesothelin release from epithelioid mesothelioma cells". Cancer Sci. 99 (3): 590–4. doi:10.1111/j.1349-7006.2007.00715.x. PMID 18167128.
• Li M, Bharadwaj U, Zhang R, Zhang S, Mu H, Fisher WE, Brunicardi FC, Chen C, Yao Q (February 2008). "Mesothelin is a malignant factor and therapeutic vaccine target for pancreatic cancer". Mol. Cancer Ther. 7 (2): 286–96. doi:10.1158/1535-7163.MCT-07-0483. PMC 2929838. PMID 18281514.
• Uehara N, Matsuoka Y, Tsubura A (February 2008). "Mesothelin promotes anchorage-independent growth and prevents anoikis via extracellular signal-regulated kinase signaling pathway in human breast cancer cells". Mol. Cancer Res. 6 (2): 186–93. doi:10.1158/1541-7786.MCR-07-0254. PMID 18245228.
• Iwahori K, Osaki T, Serada S, Fujimoto M, Suzuki H, Kishi Y, Yokoyama A, Hamada H, Fujii Y, Yamaguchi K, Hirashima T, Matsui K, Tachibana I, Nakamura Y, Kawase I, Naka T (October 2008). "Megakaryocyte potentiating factor as a tumor marker of malignant pleural mesothelioma: evaluation in comparison with mesothelin". Lung Cancer 62 (1): 45–54. doi:10.1016/j.lungcan.2008.02.012. PMID 18394747.
• Creaney J, Yeoman D, Demelker Y, Segal A, Musk AW, Skates SJ, Robinson BW (August 2008). "Comparison of osteopontin, megakaryocyte potentiating factor, and mesothelin proteins as markers in the serum of patients with malignant mesothelioma". J Thorac Oncol 3 (8): 851–7. doi:10.1097/JTO.0b013e318180477b. PMID 18670302.
• Shiomi K, Hagiwara Y, Sonoue K, Segawa T, Miyashita K, Maeda M, Izumi H, Masuda K, Hirabayashi M, Moroboshi T, Yoshiyama T, Ishida A, Natori Y, Inoue A, Kobayashi M, Sakao Y, Miyamoto H, Takahashi K, Hino O (March 2008). "Sensitive and specific new enzyme-linked immunosorbent assay for N-ERC/mesothelin increases its potential as a useful serum tumor marker for mesothelioma". Clin. Cancer Res. 14 (5): 1431–7. doi:10.1158/1078-0432.CCR-07-1613. PMID 18316566.
• Kaneko O, Gong L, Zhang J, Hansen JK, Hassan R, Lee B, Ho M (February 2009). "A binding domain on mesothelin for CA125/MUC16". J. Biol. Chem. 284 (6): 3739–49. doi:10.1074/jbc.M806776200. PMC 2635045. PMID 19075018.
• Chang MC, Chen CA, Hsieh CY, Lee CN, Su YN, Hu YH, Cheng WF (December 2009). "Mesothelin inhibits paclitaxel-induced apoptosis through the PI3K pathway". Biochem. J. 424 (3): 449–58. doi:10.1042/BJ20082196. PMID 19747165.
• Cheng WF, Huang CY, Chang MC, Hu YH, Chiang YC, Chen YL, Hsieh CY, Chen CA (April 2009). "High mesothelin correlates with chemoresistance and poor survival in epithelial ovarian carcinoma". Br. J. Cancer 100 (7): 1144–53. doi:10.1038/sj.bjc.6604964. PMC 2669998. PMID 19293794.
• Hellstrom I, Hellstrom KE (2008). "SMRP and HE4 as biomarkers for ovarian carcinoma when used alone and in combination with CA125 and/or each other". Adv. Exp. Med. Biol. Advances in Experimental Medicine and Biology 622: 15–21. doi:10.1007/978-0-387-68969-2_2. ISBN 978-0-387-68966-1. PMID 18546615.
• Bharadwaj U, Li M, Chen C, Yao Q (2008). "Mesothelin-Induced Pancreatic Cancer Cell Proliferation Involves Alteration of Cyclin E via Activation of Stat3". Mol. Cancer Res. 6 (11): 1755–65. doi:10.1158/1541-7786.MCR-08-0095. PMC 2929833. PMID 19010822.

External links

• MSLN human gene location in the UCSC Genome Browser.
• MSLN human gene details in the UCSC Genome Browser.