image: (A, B) The mRNA and protein expression of MFAP2 was significantly higher in colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ), validated through various data sources, including TCGA (A) and CPTAC (B).
(C, D) MFAP2 was significantly up-regulated in CRC patients and related to tumor progression, validated by GEPIA data.
(E) Patients with tumor recurrence were accompanied by significantly higher expression of MFAP2.
(F) CRC patients with high MFAP2 expression had significantly lower disease-free survival (DFS).
(G–J) Immunohistochemical results showed that MFAP2 was significantly overexpressed in CRC tissues, and MFAP2 expression was higher in patients with larger tumor sizes or older age.
Credit: Zhicheng He, Yuanzhi Chen, Shuting Yang, Cheng Chen, Yingying He, Shubai Liu
A recent study published in Genes & Diseases by researchers from Kunming Institute of Botany, Chinese Academy of Sciences, and Yunnan University has identified microfibril-associated protein 2 (MFAP2) as a pivotal regulator of epithelial-to-mesenchymal transition (EMT), which fuels both metastasis and chemoresistance in CRC.
Through integrated transcriptomic, proteomic, and molecular analyses, the team demonstrated that MFAP2 expression is markedly elevated in colorectal tumors, particularly in the aggressive CMS4 molecular subtype. Knockdown of MFAP2 significantly inhibited CRC cell proliferation, migration, and invasion, while enhancing sensitivity to standard first-line chemotherapies—5-fluorouracil, irinotecan, and oxaliplatin.
Mechanistic studies revealed that MFAP2 promotes EMT via activation of the EGFR–AKT–STAT3 signaling pathway, thereby fostering tumor progression and drug resistance. Silencing MFAP2 reversed EMT markers—upregulating E-cadherin and downregulating N-cadherin, vimentin, and Snail—suggesting that MFAP2 suppression can reprogram malignant cells toward a less invasive phenotype.
Moreover, clinical data showed that MFAP2 expression positively correlates with tumor stromal scores and inversely with tumor purity, implying a critical role in remodeling the tumor microenvironment. Notably, MFAP2 co-expressed strongly with biglycan (BGN) and thrombospondin 2 (THBS2)—two EMT regulators—suggesting synergistic effects in driving CRC metastasis.
To explore its therapeutic potential, the researchers performed virtual screening and molecular docking of over 10,000 compounds against MFAP2. Among these, (R,S)-ivosidenib, an FDA-approved drug for IDH1-mutant cancers, demonstrated effective MFAP2 binding and significantly impaired CRC cell migration in vitro.
In conclusion, this study identifies MFAP2 as a central regulator of EMT, metastasis, and chemotherapy resistance in colorectal cancer. These findings position MFAP2 as both a prognostic biomarker and a therapeutic target, offering new mechanistic insights and potential strategies for precision treatment—particularly for patients with the CMS4 subtype.
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