Muc4/sialomucin complex, an intramembrane modulator of ErbB2/HER2/Neu, potentiates primary tumor growth and suppresses apoptosis in a xenotransplanted tumor

Abstract

Overexpression of the membrane mucin MUC4/Sialomucin complex (SMC) has been observed during malignant progression of mammary tumors in both humans and rats, suggesting that deregulation of MUC4/SMC expression might facilitate development of these malignancies. As previously reported, overexpression of SMC results in suppression of both cell adhesion and immune killing of tumor cells. SMC also acts as a ligand for ErbB2/Neu, modulating phosphorylation of the receptor tyrosine kinase in the presence and absence of heregulin. The present studies investigated the e ect of Muc4/SMC up-regulation on primary tumor growth using a tetracycline-inducible SMC expression system in a xenotransplanted tumor model. SMC upregulation provoked rapid growth of transfected A375 melanoma in nude mice. Up-regulation of SMC, however, did not signi®cantly increase proliferation of A375 cells in vitro. Instead, a strong suppression of apoptosis was observed in situ in SMC-overexpressing tumors. These data suggest that Muc4/SMC expression promotes tumor growth in vivo at least in part via suppression of tumor cell apoptosis. Importantly, reduction of apoptosis was also observed in vitro, indicating that anti-apoptotic e ect of SMC is independent of tumor-host interactions. These ®ndings strongly suggest that SMC up-regulation alters intracellular signaling to favor cell survival, providing for the ®rst time evidence for the regulation of programmed cell death by a gene of the MUC family. Oncogene (2001) 20, 461 ± 470.

Human MUC4 mucin induces ultra-structural changes and tumorigenicity in pancreatic cancer cells

“…In our previous studies, inhibition of MUC4 expression reduced in vitro growth of pancreatic cancer cells (Singh et al, 2004). Another study performed on rat Muc4/SMC also proves the involvement of MUC4 mucin in growth advantage to cancer cells (Komatsu et al, 2001). In this study, the ectopic expression of mini-MUC4 showed an increased in vitro growth.…”

Low podoplanin expression in pretreatment biopsy material predicts poor prognosis in advanced-stage squamous cell carcinoma of the uterine cervix treated by primary radiation

“…In addition, mucin-type glycoproteins, such as podoplanin, are expressed widely on human normal cells and tumors [26][27][28] and have recently been implicated in cellular signaling, cell adhesion, tumor growth, and suppression of apoptosis. [29][30][31][32][33] We have recently characterized the immunohistochemical reactivity of tumor cells in a series of earlystage cervical squamous cell carcinomas with the D2-40 antibody and found that low levels of podoplanin expression in the tumor cells were significantly associated with the presence of lymphatic invasion and lymph node metastasis, as well as with shorter survival and higher risk of tumor recurrence. 16 Interestingly, we found that tumor emboli within lymphatic spaces, as well as metastatic tumor cells in lymph nodes, showed no podoplanin immunostaining in the vast majority of tumors, even in cases when the main tumor mass was D2-40 positive.…”

MUC4 expression is regulated by cystic fibrosis transmembrane conductance regulator in pancreatic adenocarcinoma cells via transcriptional and post-translational mechanisms

“…Despite the emerging importance of the MUC4 mucin in tumour biology (Komatsu et al, 1999(Komatsu et al, , 2001Singh et al, 2004), the molecular mechanism(s) that lead to its deregulated expression in tumour cells is largely unknown. The expression of MUC4 is developmentally regulated and varies with the degree of tissue differentiation (Buisine et al, 1998(Buisine et al, , 2000.…”

“…SMC/Muc4 acts as a ligand for ErbB2/HER2 inducing its limited phosphorylation (Jepson et al, 2002). The overexpression of SMC results in the suppression of both cell adhesion and immune killing of tumour cells, enhanced tumour growth and potentiation of metastasis (Komatsu et al, 1999(Komatsu et al, , 2000(Komatsu et al, , 2001. However, despite all these pathobiological implications of MUC4 in tumour biology, suggesting its importance as a potential therapeutic target, the molecular mechanisms implicated in its regulation have remained ill-defined.…”