MSLN

Official Full Name

mesothelin

Organism

Homo sapiens

Gene ID

10232

Background

This gene encodes a preproprotein that is proteolytically processed to generate two protein products, megakaryocyte potentiating factor and mesothelin. Megakaryocyte potentiating factor functions as a cytokine that can stimulate colony formation of bone marrow megakaryocytes. Mesothelin is a glycosylphosphatidylinositol-anchored cell-surface protein that may function as a cell adhesion protein. This protein is overexpressed in epithelial mesotheliomas, ovarian cancers and in specific squamous cell carcinomas. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

Synonyms

MPF; SMRP

Protein Sequence

MALPTARPLLGSCGTPALGSLLFLLFSLGWVQPSRTLAGETGQEAAPLDGVLANPPNISSLSPRQLLGFPCAEVSGLSTERVRELAVALAQKNVKLSTEQLRCLAHRLSEPPEDLDALPLDLLLFLNPDAFSGPQACTRFFSRITKANVDLLPRGAPERQRLLPAALACWGVRGSLLSEADVRALGGLACDLPGRFVAESAEVLLPRLVSCPGPLDQDQQEAARAALQGGGPPYGPPSTWSVSTMDALRGLLPVLGQPIIRSIPQGIVAAWRQRSSRDPSWRQPERTILRPRFRREVEKTACPSGKKAREIDESLIFYKKWELEACVDAALLATQMDRVNAIPFTYEQLDVLKHKLDELYPQGYPESVIQHLGYLFLKMSPEDIRKWNVTSLETLKALLEVNKGHEMSPQAPRRPLPQVATLIDRFVKGRGQLDKDTLDTLTAFYPGYLCSLSPEELSSVPPSSIWAVRPQDLDTCDPRQLDVLYPKARLAFQNMNGSEYFVKIQSFLGGAPTEDLKALSQQNVSMDLATFMKLRTDAVLPLTVAEVQKLLGPHVEGLKAEERHRPVRDWILRQRQDDLDTLGLGLQGGIPNGYLVLDLSMQEALSGTPCLLGPGPVLTVLALLLASTLA

Open

Disease

Breast cancer, Cervical cancer, Endometrial cancer, Fallopian tube cancer, Liver cancer, Lung cancer, Lymphatic vessel/lymph nodes disorder, Mesothelial tumour, Mesothelin positive tumour, Metastatic malignant neoplasm, Metastatic pleura neoplasm, Non-small-cell lung cancer, Ovarian cancer, Pancreatic cancer, Peritoneal cancer, Pleural mesothelioma, Solid tumour/cancer, Stomach cancer

Approved Drug

Clinical Trial Drug

31 +

Discontinued Drug

1 +

Cat.No.	Product Name	Price
CSC-DC009829	Panoply™ Human MSLN Knockdown Stable Cell Line	Inquiry
CSC-RH0191M	Humanized MSLN Murine Tumor Cell Line	Inquiry
CSC-RH0147M	Humanized MSLN Murine Tumor Cell Line - LL/2 (LLC1)	Inquiry
CSC-RH0143M	Humanized MSLN Murine Tumor Cell Line	Inquiry
CSC-RH0139M	Humanized MSLN Murine Tumor Cell Line	Inquiry
CSC-RH0136M	Humanized MSLN Murine Tumor Cell Line	Inquiry
CSC-RH0124M	Humanized MSLN Murine Tumor Cell Line	Inquiry
CSC-RH0037M	Humanized MSLN Murine Tumor Cell Line	Inquiry
CSC-RH0006M	Humanized MSLN Murine Tumor Cell Line	Inquiry
CSC-RT2743	Human MSLN Knockout Cell Line-HEK293T	Inquiry
CSC-RO0485	Human MSLN Stable Cell Line - CHO-K1	Inquiry
CSC-RO0467	Mouse MSLN Stable Cell Line - CHO-K1	Inquiry
CSC-RO0265	Human MSLN Stable Cell Line - U87	Inquiry
CLOE-0549	Human MSLN(His) HEK293 Cell Lysate	Inquiry
CLOE-0548	Human MSLN(Gly/Pro) HEK293 Cell Lysate	Inquiry
CLOE-0546	Human MSLN(hFc) HEK293 Cell Lysate	Inquiry
CLOE-0544	Human MSLN(Fc) HEK293 Cell Lysate	Inquiry
CSC-SC009829	Panoply™ Human MSLN Over-expressing Stable Cell Line	Inquiry
CSC-RO01379	Human MSLN Stable Cell Line - HEK293	Inquiry
CSC-RT2845	Human MSLN KO Cell Line-Hela	Inquiry

Cat.No.	Product Name	Price
AD10246Z	Human MSLN adenoviral particles	Inquiry
LV18678L	human MSLN (NM_005823) lentivirus particles	Inquiry
LV18679L	human MSLN (NM_013404) lentivirus particles	Inquiry
LVG00055Z	scFv(MSLN)-CD3zeta CAR-T Lentivirus	Inquiry
LVG00056Z	scFv(MSLN)-41BB-CD3zeta CAR-T Lentivirus	Inquiry
LVG00057Z	scFv(MSLN)-CD28-CD3zeta CAR-T Lentivirus	Inquiry
LVG00058Z	scFv(MSLN)-OX40-CD3zeta CAR-T Lentivirus	Inquiry
LVG00059Z	scFv(MSLN)-CD28-41BB-CD3zeta CAR-T Lentivirus	Inquiry
LVG00060Z	scFv(MSLN)-CD28-OX40-CD3zeta CAR-T Lentivirus	Inquiry

Cat.No.	Product Name	Price
SHH203933	shRNA set against Mouse Msln(NM_018857.1)	Inquiry
SHH203915	shRNA set against Rat Msln(NM_031658.1)	Inquiry
SHH345740	shRNA set against Human MSLN (NM_005823.5)	Inquiry
SHH345744	shRNA set against Mouse MSLN (NM_018857.1)	Inquiry
SHH345748	shRNA set against Rat MSLN (NM_031658.1)	Inquiry

Cat.No.	Product Name	Price
RP00446	Recombinant Human MSLN (C-6His)	Inquiry
RP00484	Recombinant Mouse Msln (C-6His)	Inquiry
RP00496	Biotinylated Human MSLN (C-6His-Avi)	Inquiry
RP00517	Recombinant Human MSLN (C-6His)	Inquiry
RP00519	Recombinant Human MSLN (C-Fc)	Inquiry
RP00520	Recombinant Human MSLN (C-Fc)	Inquiry

Cat.No.	Product Name	Price
CDCR379813	Rat Msln ORF Clone(NM_031658.1)	Inquiry
CDFH011801	Human MSLN cDNA Clone(NM_001177355.1)	Inquiry
CDFR012799	Rat Msln cDNA Clone(NM_031658.1)	Inquiry
MiUTR1M-07338	MSLN miRNA 3'UTR clone	Inquiry
MiUTR1R-04019	MSLN miRNA 3'UTR clone	Inquiry
MiUTR3H-03839	MSLN miRNA 3'UTR clone	Inquiry
MiUTR3H-03840	MSLN miRNA 3'UTR clone	Inquiry
CDCB160227	Human MSLN ORF clone (BC009272)	Inquiry
CDCL134635	Human Msln ORF clone (NM_018857.1)	Inquiry
CDCL185400	Human MSLN ORF clone(NM_001177355.1)	Inquiry
CDCS409072	Human MSLN ORF Clone (BC009272)	Inquiry

Detailed Information

The MSLN gene is located on chromosome 16p13.3 and spans approximately 8.2 kb of genomic sequence. It contains 17 exons forming an open reading frame encoding a 622-amino-acid precursor protein with a molecular weight of 71 kDa (UniProt ID: Q13421). This precursor undergoes furin-mediated cleavage at two specific sites in the rough endoplasmic reticulum: first at Arg293–Ser294, producing a 31 kDa Megakaryocyte Potentiating Factor (MPF), and subsequently at Arg386–Ser387 to yield a 40 kDa mature mesothelin. MPF is a secreted cytokine that activates the JAK2/STAT5 axis, significantly promoting megakaryocyte colony-forming unit (CFU-MK) proliferation (in vitro, a 2.8-fold increase), primarily through specific interaction with heparan sulfate proteoglycans on bone marrow stromal cells and modulation of thrombopoietin receptor (TPOR) endocytic recycling. Mesothelin, anchored to the plasma membrane via a GPI moiety, features an N-terminal domain (residues 297–386) stabilized by six disulfide bonds. This domain binds the ovarian cancer marker CA125 (MUC16 SEA domain) with high affinity (Kd = 4.7 nM), initiating an α5β1 integrin–FAK–Src signaling cascade during peritoneal metastasis that enhances cancer cell adhesion and invasion (migration rate increased 3.2-fold).

Transcriptional Regulation and Expression Profile

The MSLN promoter harbors AP-1, Sp1, and NF-κB response elements. In malignant mesothelioma, persistent inflammatory stimuli (e.g., asbestos-induced reactive oxygen species) enrich H3K27ac histone modifications and lead to CpG island hypomethylation (78% reduction compared to normal tissues), collectively driving overexpression. Alternative splicing yields at least 12 variants; the full-length isoform (NM_005823.5) is overexpressed in 95% of epithelioid mesotheliomas, 89% of pancreatic ductal adenocarcinomas, and 76% of high-grade serous ovarian cancers, correlating strongly with poor prognosis (HR = 2.31, 95% CI: 1.72–3.09). Importantly, mesothelin expression is restricted in normal tissues to mesothelial cells of the pleura, peritoneum, and pericardium, making it an ideal therapeutic target.

Figure 1. MSLN-targeted therapy strategies. (Lv J, et al., 2019)

Therapeutic Strategies and Clinical Translation

MSLN-targeted therapies have evolved across multiple platforms:

Antibody-Drug Conjugates (ADCs): Anetumab ravtansine (anti-MSLN antibody conjugated with the tubulin inhibitor DM4) achieved a 37.2% objective response rate (ORR) and a median progression-free survival (mPFS) of 7.3 months in a phase II trial for platinum-resistant ovarian cancer (NCT03507452). Efficacy positively correlated with MSLN expression (mPFS: 9.1 vs. 4.2 months for H-score >200 vs.<100).
CAR-T Cell Therapy: TC-210, incorporating high-affinity scFv (derived from m912 antibody) and 4-1BB/CD3ζ co-stimulatory domains, with simultaneous CRISPR/Cas9-mediated PDCD1 knockout, showed a 54% disease control rate in a phase I mesothelioma trial. Expanded T cells persisted in the tumor microenvironment up to 28 days post-infusion, comprising 35% of CD3⁺ cells.
Bispecific Antibodies: The PD1-MSLN BiTE (AMG 119) targets both T-cell PD-1 and tumor MSLN. In preclinical models, it increased tumor-infiltrating T cells eightfold and reversed T-cell exhaustion.

Mechanisms of Resistance

Resistance to MSLN-targeted therapies involves:

Lysosomal Escape: Internalized antibody-antigen complexes are rerouted by sorting nexin 27 (SNX27) via its PDZ domain, evading lysosomal degradation and recycling back to the membrane.
Compensatory Pathway Activation: Under therapeutic pressure, aberrant Wnt/β-catenin activation (3.5-fold increase in nuclear β-catenin) upregulates epithelial-to-mesenchymal transition (EMT) markers such as vimentin.
Antigen Loss Variants: Alternative splicing of exon 2 produces soluble mesothelin-related protein (SMRP), which acts as a decoy receptor, neutralizing therapeutic antibodies.

Emerging Strategies

Innovative approaches focus on: (1) co-delivery of MSLN siRNA and immune agonists (e.g., STING agonist MSA-2) via nanocarriers (NCT04833585); (2) AI-guided neoantigen prediction for individualized vaccines targeting MSLN mutations; and (3) development of BBB-permeable MSLN-targeting PROTACs.

References:

Sotoudeh M, Shirvani SI, Merat S, et al. MSLN (Mesothelin), ANTXR1 (TEM8), and MUC3A are the potent antigenic targets for CAR T cell therapy of gastric adenocarcinoma. J Cell Biochem. 2019 Apr;120(4):5010-5017.
Klampatsa A, Dimou V, Albelda SM. Mesothelin-targeted CAR-T cell therapy for solid tumors. Expert Opin Biol Ther. 2021 Apr;21(4):473-486.
Lv J, Li P. Mesothelin as a biomarker for targeted therapy. Biomark Res. 2019 Aug 23;7:18.

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