MUC13 drives cancer aggressiveness and metastasis through the YAP1-dependent pathway (original) (raw)
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MUC1 extracellular domain confers resistance of epithelial cancer cells to anoikis
Cell death & disease, 2014
Anoikis, a special apoptotic process occurring in response to loss of cell adhesion to the extracellular matrix, is a fundamental surveillance process for maintaining tissue homeostasis. Resistance to anoikis characterises cancer cells and is a pre-requisite for metastasis. This study shows that overexpression of the transmembrane mucin protein MUC1 prevents initiation of anoikis in epithelial cancer cells in response to loss of adhesion. We show that this effect is largely attributed to the elongated and heavily glycosylated extracellular domain of MUC1 that protrudes high above the cell membrane and hence prevents activation of the cell surface anoikis-initiating molecules such as integrins and death receptors by providing them a mechanically 'homing' microenvironment. As overexpression of MUC1 is a common feature of epithelial cancers and as resistance to anoikis is a hallmark of both oncogenic epithelial-mesenchymal transition and metastasis, MUC1-mediated cell resistanc...
Targeting YAP-Dependent MDSC Infi ltration Impairs Tumor Progression
The signaling mechanisms between prostate cancer cells and infi ltrating immune cells may illuminate novel therapeutic approaches. Here, utilizing a prostate adenocarcinoma model driven by loss of Pten and Smad4 , we identify polymorphonuclear myeloid-derived suppressor cells (MDSC) as the major infi ltrating immune cell type, and depletion of MDSCs blocks progression. Employing a novel dual reporter prostate cancer model, epithelial and stromal transcriptomic profi ling identifi ed CXCL5 as a cancer-secreted chemokine to attract CXCR2-expressing MDSCs, and, correspondingly, pharmacologic inhibition of CXCR2 impeded tumor progression. Integrated analyses identifi ed hyperactivated Hippo-YAP signaling in driving CXCL5 upregulation in cancer cells through the YAP-TEAD complex and promoting MDSC recruitment. Clinicopathologic studies reveal upregulation and activation of YAP1 in a subset of human prostate tumors, and the YAP1 signature is enriched in primary prostate tumor samples with stronger expression of MDSC-relevant genes. Together, YAPdriven MDSC recruitment via heterotypic CXCL5-CXCR2 signaling reveals an effective therapeutic strategy for advanced prostate cancer.
Role of MUC4–NIDO domain in the MUC4-mediated metastasis of pancreatic cancer cells
Oncogene, 2012
MUC4 is a large transmembrane type I glycoprotein that is overexpressed in pancreatic cancer (PC) and has been shown to be associated with its progression and metastasis. However, the exact cellular and molecular mechanism(s) through which MUC4 promotes metastasis of PC cells has been sparsely studied. Here we showed that the NIDO domain of MUC4, which is similar to the G1-domain present in the nidogen or entactin (an extracellular matrix protein), contributes to the protein-protein interaction property of MUC4. By this interaction, MUC4 promotes breaching of basement membrane integrity, and spreading of cancer cells. These observations are corroborated with the data from our study using an engineered MUC4 protein without the NIDO domain, which was ectopically expressed in the MiaPaCa PC cells, lacking endogenous MUC4 and nidogen protein. The in vitro studies demonstrated an enhanced invasiveness of MiaPaCa cells expressing MUC4 (MiaPaCa-MUC4) compared to vector-transfected cells (MiaPaCa-Vec; p=0.003) or cells expressing MUC4 without the NIDO domain (MiaPaCa-MUC4-NIDO Δ ; p=0.03). However, the absence of NIDO-domain has no significant role on cell growth and motility (p=0.93). In the invivo studies, all the mice orthotopically implanted with MiPaCa-MUC4 cells developed metastasis to the liver as compared to MiaPaCa-Vec or the MiaPaCa-MUC4-NIDO Δ group, hence, supporting our in vitro observations. Additionally, a reduced binding (p=0.0004) of MiaPaCa-MUC4-NIDO Δ cells to the fibulin-2 coated plates compared to MiaPaCa-MUC4 cells indicated a possible interaction between the MUC4-NIDO domain and fibulin-2, a nidogen-interacting protein. Furthermore, in PC tissue samples, MUC4 colocalized with the fibulin-2 present in the basement membrane. Altogether, our findings demonstrate that the MUC4-NIDO domain significantly contributes to the MUC4-mediated metastasis of PC cells. This may be partly due to the interaction between the MUC4-NIDO domain and fibulin-2.
Annals of Colorectal Research, 2019
Yes-associated protein (YAP1), the downstream effector of the Hippo pathway, plays important roles in the regulation of tissue reconstruction, stem cell proliferation, and development of different cancers. The regulation of YAP1 phosphorylation, YAP1 expression level, and its cellular localization have been considered in cancer development. There are different experimental evidences that indicate that YAP1 activation results in tumorigenesis, tumor progression, and metastasis. YAP1 is a transcription co-activator, and its dysregulation has been suggested in various cancers including colorectal cancer (CRC). The localization of YAP1 in the nucleus results in YAP1 interactions with different transcription factors to promote the expression of genes involved in cell proliferation, metastasis, and stem cell maintenance. However, a number of studies have been reported the tumor suppressor role of YAP1 in CRC. Therefore, a better understanding of the YAP1 regulation could be helpful for prevention, diagnosis, and treatment of CRC. In this review, we will discuss different roles of YAP1 in CRC progression through the regulatory roles of long non-coding RNAs (LncRNAs), microRNAs (miRNAs) and circular RNAs (CircRNAs) in YAP1 regulation.
FGF8 promotes colorectal cancer growth and metastasis by activating YAP1
Oncotarget, 2014
Colorectal cancer (CRC) is a major cause of cancer-related death worldwide. The poor prognosis of CRC is mainly due to uncontrolled tumor growth and distant metastases. In this study, we found that the level of FGF8 was elevated in the great majority of CRC cases and high FGF8 expression was significantly correlated with lymph nodes metastasis and worse overall survival. Functional studies showed that FGF8 can induce a more aggressive phenotype displaying epithelial-to-mesenchymal transition (EMT) and enhanced invasion and growth in CRC cells. Consistent with this, FGF8 can also promote tumor growth and metastasis in mouse models. Bioinformatics and pathological analysis suggested that YAP1 is a potential downstream target of FGF8 in CRC cells. Molecular validation demonstrated that FGF8 fully induced nuclear localization of YAP1 and enhanced transcriptional outcomes such as the expression of CTGF and CYR61, while decreasing YAP1 expression impeded FGF-8-induced cell growth, EMT, mi...
Carcinogenesis, 2009
Mucins play a key role in tumorigenesis. MUC15 is a membrane-bound mucin and the MUC15 messenger RNA (mRNA) has been detected in various organs. However, its role in tumor malignancy is still unclear. This study was to investigate the MUC15 expression in colorectal tumors and the role of MUC15 in colon cancer cells. We found that the mRNA expression of MUC15 was significantly higher in 70.8% (51/72) of colorectal tumors compared with their normal counterparts by real-time reverse transcription-polymerase chain reaction. Immunohistochemistry showed that MUC15 expression was increased in 82.6% (43/52) of colorectal tumors. MUC15 overexpression in HCT116 cells enhanced cell proliferation, cell-extracellular matrix adhesion, colony-forming ability and invasion. Furthermore, these effects were significantly reversed by knockdown of MUC15 with short-hairpin RNA. In nude mice models, MUC15 overexpression significantly (P < 0.01) enhanced tumor growth. In addition, treatment of PD98059 significantly (P < 0.01) inhibited MUC15-enhanced invasion, suggesting that the invasion induced by MUC15 in HCT116 cells was primarily mediated through activation of extracellular signal-regulated kinase 1/2. In conclusion, these results suggest that MUC15 is upregulated in colorectal tumors and its expression enhances the oncogenic potential of colon cancer cells.
Molecular Cancer Research, 2022
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer, as it commonly metastasizes to the liver resulting in an overall poor prognosis. However, the molecular mechanism involved in liver metastasis remains poorly understood. Here, we aimed to identify the MUC16-mediated molecular mechanism of PDAC-liver metastasis. Previous studies demonstrated that MUC16 and its C-terminal (Cter) domain are involved in the aggressiveness of PDAC. In the present study, we observed MUC16 and its Cter expression significantly high in human PDAC tissues, PDAC organoids, and metastatic liver tissues, while no expression was observed in normal pancreatic tissues using immunohistochemistry (IHC) and immunofluorescence (IFC) analyses. MUC16 knockdown in SW1990 and CD18/HPAF PDAC cells significantly decreased the colony formation, migration, and endothelial/p-selectin binding. In contrast, MUC16-Cter ectopic overexpression showed significantly increased colony formation and motility in MiaPaCa2 PC cells. Interestingly, MUC16 promoted cell survival and colonization in the liver, mimicking an ex vivo environment. Furthermore, MUC16 enhanced liver metastasis in the in vivo mouse model. Our integrated analyses of RNA-seq suggested that MUC16 alters Neuropilin-2 (NRP2) and cell adhesion molecules in PC cells. Furthermore, we identified that MUC16 regulated NRP2 via JAK2/STAT1 signaling in PDAC. NRP2 knockdown in MUC16 overexpressed PDAC cells showed significantly decreased cell adhesion and migration. Overall, the findings indicate that MUC16 regulates NRP2 and induces metastasis in PDAC.Implications:This study shows that MUC16 plays a critical role in PDAC liver metastasis by mediating NRP2 regulation by JAK2/STAT1 axis, thereby paving the way for future therapy efforts for metastatic PDAC.
MACC1—the first decade of a key metastasis molecule from gene discovery to clinical translation
Cancer and Metastasis Reviews, 2019
Deciphering the paths to metastasis and identifying key molecules driving this process is one important issue for understanding and treatment of cancer. Such a key driver molecule is Metastasis Associated in Colon Cancer 1 (MACC1). A decade long research on this evolutionarily conserved molecule with features of a transcription factor as well as an adapter protein for versatile protein-protein interactions has shown that it has manifold properties driving tumors to their metastatic stage. MACC1 transcriptionally regulates genes involved in epithelial-mesenchymal transition (EMT), including those which are able to directly induce metastasis like c-MET, impacts tumor cell migration and invasion, and induces metastasis in solid cancers. MACC1 has proven as a valuable biomarker for prognosis of metastasis formation linked to patient survival and gives promise to also act as a predictive marker for individualized therapies in a broad variety of cancers. This review discusses the many features of MACC1 in the context of the hallmarks of cancer and the potential of this molecule as biomarker and novel therapeutic target for restriction and prevention of metastasis.
Functions and regulation of MUC13 mucin in colon cancer cells
Journal of Gastroenterology, 2013
Background-MUC13 is over-expressed and aberrantly localized in colon cancer tissue; however, the specific functions and regulation of MUC13 expression are unknown. Methods-Stable cell lines with either over-expressed or suppressed MUC13 levels were analyzed to determine cell growth, colony formation, cell migration, and cell invasion assays. The molecular mechanisms involved in MUC13 regulation were elucidated via chromatin immunoprecipitation (ChIP) and analysis of interleukin 6 (IL6) treatments. Colon cancer tissues were analyzed by immunohistochemistry (IHC) for the protein levels of MUC13 and P-STAT5 in colon cancer cells. Results-Over-expression of MUC13 increased cell growth, colony formation, cell migration, and invasion. In concordance, MUC13 silencing decreased these tumorigenic features. Overexpression of MUC13 also modulated various cancer-associated proteins, including telomerase reverse transcriptase (TERT), sonic hedgehog (SHH), B cell lymphoma murine like site 1 (BMI-1), and GATA like transcription factor 1 (GATA1). Additionally, MUC13 over-expressing cells showed increased HER2 and PERK expression. ChIP analysis revealed binding of STAT5 to the predicted MUC13 promoter. IL6 treatment of colon cancer cells increased the expression of MUC13 via activation of JAK2/STAT5 signaling pathway. Suppression of JAK2 and STAT5 signaling by chemical inhibitors abolished IL6 induced MUC13 expression. IHC analysis showed