MUC6, a mucin-encoding gene, is involved in maintaining the integrity of the gastric mucus barrier. It is expressed in the gastric epithelium and duodenal Brunner's glands, where it binds to TFF2, a trefoil factor family member, through non-covalent lectin interactions and possibly disulfide bridges, stabilizing the mucus barrier [3].

MUC6 has been associated with multiple diseases. In Alzheimer's disease, MUC6 VNTR repeat expansion is linked to AD pathologic severity, especially tau proteinopathy, and may influence AP2A2 gene expression [1]. In endocervical gastric-type adenocarcinoma, MUC6 has been used as an immunohistochemical marker with moderate specificity and low sensitivity [2]. In lung invasive mucinous adenocarcinoma, MUC6 expression is a preferable prognostic biomarker, as MUC6-expressing cells show lower proliferation, motility, and invasiveness [4]. In gastric cancer, MUC6 promoter methylation downregulates its expression, promoting cancer progression [5]. In pancreatic cancer, αGlcNAc-bound MUC6 suppresses malignancy, and decreased expression may serve as a biomarker of tumor progression [7]. In hepatocellular carcinoma, MUC6 genetic variants may be related to the disease and its progression [8].

In conclusion, MUC6 is crucial for maintaining the gastric mucus barrier. Its role in multiple diseases, including Alzheimer's, various cancers, and potentially peptic ulcer disease as suggested by GWAS [6], is significant. Functional studies related to MUC6, especially those using genetic models, can provide insights into disease mechanisms and may offer new directions for diagnosis and treatment.

References:

1. Nelson, Peter T, Fardo, David W, Katsumata, Yuriko. . The MUC6/AP2A2 Locus and Its Relevance to Alzheimer's Disease: A Review. In Journal of neuropathology and experimental neurology, 79, 568-584. doi:10.1093/jnen/nlaa024. https://pubmed.ncbi.nlm.nih.gov/32357373/

2. Fulgione, Caterina, Raffone, Antonio, Travaglino, Antonio, Mascolo, Massimo, Zannoni, Gian Franco. 2022. Diagnostic accuracy of HIK1083 and MUC6 as immunohistochemical markers of endocervical gastric-type adenocarcinoma: A systematic review and meta-analysis. In Pathology, research and practice, 241, 154261. doi:10.1016/j.prp.2022.154261. https://pubmed.ncbi.nlm.nih.gov/36527837/

3. Hoffmann, Werner. 2015. TFF2, a MUC6-binding lectin stabilizing the gastric mucus barrier and more (Review). In International journal of oncology, 47, 806-16. doi:10.3892/ijo.2015.3090. https://pubmed.ncbi.nlm.nih.gov/26201258/

4. Yamanoi, Kazuhiro, Fujii, Chifumi, Yuzuriha, Hanae, Asamura, Hisao, Nakayama, Jun. 2022. MUC6 expression is a preferable prognostic marker for invasive mucinous adenocarcinoma of the lung. In Histochemistry and cell biology, 157, 671-684. doi:10.1007/s00418-022-02093-1. https://pubmed.ncbi.nlm.nih.gov/35353213/

5. Shi, Ding, Xi, Xiao-Xia. . Regulation of MUC6 Methylation Correlates with Progression of Gastric Cancer. In Yonsei medical journal, 62, 1005-1015. doi:10.3349/ymj.2021.62.11.1005. https://pubmed.ncbi.nlm.nih.gov/34672134/

6. Wu, Yeda, Murray, Graham K, Byrne, Enda M, Visscher, Peter M, Wray, Naomi R. 2021. GWAS of peptic ulcer disease implicates Helicobacter pylori infection, other gastrointestinal disorders and depression. In Nature communications, 12, 1146. doi:10.1038/s41467-021-21280-7. https://pubmed.ncbi.nlm.nih.gov/33608531/

7. Yuki, Atsuko, Fujii, Chifumi, Yamanoi, Kazuhiro, Kawakubo, Masatomo, Nakayama, Jun. 2021. Glycosylation of MUC6 by α1,4-linked N-acetylglucosamine enhances suppression of pancreatic cancer malignancy. In Cancer science, 113, 576-586. doi:10.1111/cas.15209. https://pubmed.ncbi.nlm.nih.gov/34808019/

8. Lee, Hsiang-Lin, Chien, Yi-Chung, Wang, Hsiang-Ling, Yang, Shun-Fa, Yu, Yung-Luen. 2022. Analysis of MUC6 Genetic Variants on the Clinicopathologic Characteristics of Patients with Hepatocellular Carcinoma. In Journal of Cancer, 13, 3251-3257. doi:10.7150/jca.75754. https://pubmed.ncbi.nlm.nih.gov/36118520/