Disease relevance of MUC4

• IPMTs of adenoma (dysplasia) type exhibited high expression of MUC2 (93%), MUC5AC (97%), and, to a lesser extent, of MUC4 (71%), all of which were also observed in colloid carcinomas associated with IPMTs [1].
• These observations imply important functions for MUC4 in both normal mammary function and in breast cancer [2].
• All mucoepidermoid carcinomas expressed MUC1, and 38/40 tumors expressed MUC4 [3].
• In contrast, MUC4 was strongly expressed in gallbladder adenocarcinomas [4].
• MUC4 is the earlier mucin gene expressed in the foregut, before epithelial differentiation and is expressed independently of mucus secretion both in normal adult airways and carcinomas [5].

High impact information on MUC4

• MUC4 splice variants are overexpressed in several tumours; in particular, they are highly expressed in pancreatic carcinomas but not in normal pancreas [6].
• This domain occurs in putative cell adhesion molecules and in some splice variants of MUC4 [6].
• MUC2, MUC4, and MUC5AC are generally undetectable in all cells of normal pancreas tissue [7].
• In pancreas cancer tissues and cell lines, increased expression of MUC2, MUC4, and MUC5C is shown [8].
• Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin-resistant, MUC4-expressing breast cancer cell line [9].

Chemical compound and disease context of MUC4

• The MUC4 mucin is a transmembrane glycoprotein that is implicated in the pathogenesis of pancreatic cancer and is aberrantly expressed in many other epithelial carcinomas [10].
• The univariate analysis showed that high MUC4 expression (P = 0.0072), high MUC1 expression (P = 0.0092), histologic grading (P = 0.0029), surgical margin involvement (P = 0.0137), and nodal metastasis (P = 0.0036) were statistically significant risk factors [11].
• MUC4 (sialomucin complex) expression in salivary gland tumors and squamous cell carcinoma of the upper aerodigestive tract [12].
• Growth inhibition assays using melanoma cell lines that either express the glycoprotein (Muc4(+)) or do not (Muc4(-)) showed that Muc4 renders cells resistant to taxol, doxorubicin, vinblastine, rhodamine 123, and 2-deoxyglucose [13].
• We have previously demonstrated that Muc4, a transmembrane mucin that promotes tumor growth and metastasis, physically interacts with the ErbB2 receptor tyrosine kinase and augments receptor tyrosine phosphorylation in response to the neuregulin-1beta (NRG1beta) growth factor [14].

Biological context of MUC4

• While most mucin genes were downregulated in severely dysplastic and neoplastic tissues, there was upregulation of the membrane bound mucins MUC1 and MUC4 [15].
• MUC4 expression was seen at a low level in the colonic epithelium from 13 weeks of gestation but not elsewhere in the gastrointestinal tract [16].
• Major expression of MUC4 and MUC5B consistent with an endocervical phenotype was observed in seven benign (64%) and three borderline (30%) tumours [17].
• MUC4 expression correlated with squamous cell differentiation [18].
• No alteration in MUC3 or MUC4 gene expression was detectable in UC compared with normal colorectal mucosa [19].

Anatomical context of MUC4

• During this developmental stage, MUC1 and MUC4 mRNAs are located in goblet and ciliated cells, whereas MUC2 mRNAs are located in basal and goblet cells [20].
• Although MUC4 is encoded by a single gene, it is produced by epithelial cells as a heterodimer through a proteolytic cleavage mechanism [2].
• Functionally, MUC4 is proposed to provide a protective mechanism for vulnerable epithelia, such as those of the airway, eye, female reproductive tract and mammary gland [2].
• Both MUC1 and MUC4 were up-regulated in transposed ileal segments, genes expressed by the normal human urothelium [21].
• CONCLUSION: Transposition of ileal segments into the urinary tract results in up-regulation of MUC1 and MUC4, the predominant MUC genes expressed in the human bladder [21].

Associations of MUC4 with chemical compounds

• Northern blot analysis showed a similar increase for MUC4 and demonstrated that induction of MUC4 and MUC5B expression depended on retinoic acid [22].
• Second, MUC4 can bind the receptor tyrosine kinase ErbB2 and alter its cellular signaling [2].
• As a luminal surface component, the MUC4 is situated to contribute to the non-adhesive luminal surface and to act as an intrinsic protection and survival factor [23].
• To determine whether RA-associated MUC4 mRNA induction is a direct or indirect effect, HCjE cells were treated with RA and the protein synthesis inhibitor cycloheximide (1.0 microg/mL) for 12 hours [24].
• When correlated with plasma steroid levels, message levels of both MUC4 and MUC5B were inversely related to progesterone levels [25].

Regulatory relationships of MUC4

• Expression of MUC4 in mammary gland is repressed by posttranscriptional mechanisms involving basement membrane and TGF-beta, which are relieved during pregnancy to permit secretion of MUC4 into milk [2].
• Pan-JAK inhibitor revealed marked reduction in IL-4 stimulated MUC4 levels and JAK3 selective inhibitor down-regulated MUC4 mRNA expression in a concentration-dependent fashion [26].

Other interactions of MUC4

• There was no association between MUC1 or MUC4 expression and MSI status [27].
• Northern blot analysis confirmed the expression of MUC7 in the human trachea and MUC4 in the human submandibular gland [28].
• By means of luciferase assay, GATA-5 was found to activate the promoters of the human MUC2 and MUC4 genes [29].
• These findings indicate that MUC1, MUC4 and MUC16 evolved from distinct ancestors and that the membrane-bound mucins consist of different subgroups based on their genetic backgrounds [30].
• The mucins, MUC1-7, are found with variable distribution in different body tissues; MUC4, MUC5AC and MUC6 are typically found in gastric mucosa [31].

Analytical, diagnostic and therapeutic context of MUC4

• Immunohistochemistry also suggested the presence of MUC4 in human colonic goblet cells [32].
• Finally, MUC4 expression in the three types of endothelial cell lines was confirmed by reverse transcription-polymerase chain reaction (RT-PCR) [23].
• Real-time PCR revealed that MUC4 mRNA was significantly induced by serum 3 hours after its addition, and that MUC1 and MUC16 mRNA levels were significantly upregulated at 72 hours [24].
• This expression of MUC4 in endothelial cells was confirmed by immunoblotting with 1G8 in human umbilical vein endothelial cells (HUVECs), human iliac artery endothelial cells (HIAECs), and human microvascular endothelial cells (HMVECs) [23].
• We studied expression of MUC1, MUC2, and MUC4 apomucins in a series of normal colon biopsies using a combination of immunoelectron microscopy and light microscopy [33].

References