Mesothelin

MSLN
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesMSLN, MPF, SMRP, mesothelin
External IDsOMIM: 601051 MGI: 1888992 HomoloGene: 4249 GeneCards: MSLN
Gene location (Human)
Chr.Chromosome 16 (human)[1]
Band16p13.3Start760,762 bp[1]
End768,865 bp[1]
Orthologs
SpeciesHumanMouse
Entrez

10232

56047

Ensembl

ENSG00000102854

ENSMUSG00000063011

UniProt

Q13421

Q61468

RefSeq (mRNA)

NM_001177355
NM_005823
NM_013404

NM_018857
NM_001356286

RefSeq (protein)

NP_001170826
NP_005814
NP_037536

NP_061345
NP_001343215

Location (UCSC)Chr 16: 0.76 – 0.77 MbChr 17: 25.75 – 25.75 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Mesothelin, also known as MSLN, is a protein that in humans is encoded by the MSLN gene.[5][6]

Function

Mesothelin is a 40 kDa protein that is expressed in mesothelial cells.[7] The protein was first identified by its reactivity with monoclonal antibody K1.[8] 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.[9] A knockout mouse line that lacks mesothelin reproduces and develops normally.[10]

Mesothelin is over expressed in several human tumors, including mesothelioma and ovarian and pancreatic adenocarcinoma.[7] The interaction between mesothelin and MUC16 (also known as CA125) may facilitate the implantation and peritoneal spread of tumors by cell adhesion. The region (296-359) consisting of 64 amino acids at the N-terminal of cell surface mesothelin is the functional binding domain for MUC16.[11]

Medical applications

Mesothelin is a tumour differentiation antigen that is normally present on the mesothelial cells lining the pleura, peritoneum and pericardium.[12] 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.[9][12] A 2016 review indicates that some immunotherapeutic strategies have shown encouraging results in early-phase clinical trials. [13] Elevations of serum mesothelin specific to ovarian and other cancer patients may be measured using ELISA assays.[14] Assays for blood-borne mesothelin and MPF for tumor diagnosis, especially applied to asbestos-related mesothelioma have been developed.[15] Elevated serum mesothelin was found in most patients with mesothelioma (71%) and ovarian cancer (67%).[16] 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).[17] Circulating mesothelin is reported in nearly all pancreatic cancers,[18] 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.[19] It was noted that the cutoff levels for normal could differ as much as 10-fold among publications, depending on the assay used[19][17][16] and thus that normal levels must be determined anew when new assays are introduced.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000102854 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000063011 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. ↑ 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.
  6. ↑ 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. Bibcode:1996PNAS...93..136C. doi:10.1073/pnas.93.1.136. PMC 40193. PMID 8552591.
  7. 1 2 Hassan R, Ho M (January 2008). "Mesothelin targeted cancer immunotherapy". European Journal of Cancer. 44 (1): 46–53. doi:10.1016/j.ejca.2007.08.028. PMC 2265108. PMID 17945478.
  8. ↑ 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 Research. 52 (1): 181–6. PMID 1727378.
  9. 1 2 Hassan R, Bera T, Pastan I (June 2004). "Mesothelin: a new target for immunotherapy". Clinical Cancer Research. 10 (12 Pt 1): 3937–42. doi:10.1158/1078-0432.CCR-03-0801. PMID 15217923.
  10. ↑ Bera TK, Pastan I (2000). "Mesothelin is not required for normal mouse development or reproduction". Molecular and Cellular Biology. 20 (8): 2902–6. doi:10.1128/MCB.20.8.2902-2906.2000. PMC 85523. PMID 10733593.
  11. ↑ Kaneko O, Gong L, Zhang J, Hansen JK, Hassan R, Lee B, Ho M (February 2009). "A binding domain on mesothelin for CA125/MUC16". The Journal of Biological Chemistry. 284 (6): 3739–49. doi:10.1074/jbc.M806776200. PMC 2635045. PMID 19075018.
  12. 1 2 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.
  13. ↑ Morello A, Sadelain M, Adusumilli PS (2016). "Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors". Cancer Discovery. 6 (2): 133–46. doi:10.1158/2159-8290.CD-15-0583. PMC 4744527. PMID 26503962.
  14. ↑ 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.
  15. ↑ Maeda M, Hino O (2006). "Blood tests for asbestos-related mesothelioma". Oncology. 71 (1–2): 26–31. doi:10.1159/000100446. PMID 17344668.
  16. 1 2 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.
  17. 1 2 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.
  18. ↑ 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.
  19. 1 2 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.
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