MUC1 extracellular domain confers resistance of epithelial cancer cells to anoikis.
Ontology highlight
ABSTRACT:
SUBMITTER: Zhao Q
PROVIDER: S-EPMC4649521 | biostudies-other | 2014 Oct
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Denial of the appropriate cell-matrix interaction in epithelial cells induces apoptosis and is called 'anoikis'. Cancer cells are resistant to anoikis and it is believed that the resistance to anoikis helps promote tumor malignancy especially metastasis. We and others have demonstrated that the expression of tight junction protein claudin-1 is highly upregulated in colorectal cancer (CRC) and helps promote tumor progression and metastasis. However, molecular mechanism/s underlying claudin-1-dependent regulation of CRC progression remains poorly understood. In current study, we have determined that claudin-1 expression modulates anoikis in colon cancer cells to influence colon cancer invasion and thus metastasis. We have further provided data that claudin-1 modulates anoikis in a Src-Akt-Bcl-2-dependent manner. Importantly, claudin-1 physically associates with Src/p-Src in a multiprotein complex that also includes ZO-1, a PDZ-binding tight junction protein. Taken together, our data support the role of claudin-1 in the regulation of CRC progression and suggest that the regulation of anoikis may serve as a key regulatory mechanism in claudin-1-dependent regulation of CRC progression. Our findings are of direct clinical relevance and may open new therapeutic opportunity in colon cancer treatment and/or management.
| S-EPMC3510734 | biostudies-literature
Project description:We studied the susceptibility of primary ovarian cancer cells to oncolytic adenoviruses. Using gene expression profiling of cancer cells either resistant or susceptible to viral oncolysis, we discovered that the epithelial phenotype of ovarian cancer represents a barrier to infection by commonly used oncolytic adenoviruses targeted to coxsackie-adenovirus receptor or CD46. Specifically, we found that these adenovirus receptors were trapped in tight junctions and not accessible for virus binding. Accessibility to viral receptors was critically linked to depolarization and the loss of tight and adherens junctions, both hallmarks of epithelial-to-mesenchymal transition (EMT). We showed that specific, thus far little-explored adenovirus serotypes (Ad3, Ad7, Ad11, and Ad14) that use receptor(s) other than coxsackie-adenovirus receptor and CD46 were able to trigger EMT in epithelial ovarian cancer cells and cause efficient oncolysis. Our studies on ovarian cancer cultures and xenografts also revealed several interesting cancer cell biology features. Tumors in situ as well as tumor xenografts in mice mostly contained epithelial cells and cells that were in a hybrid stage where they expressed both epithelial and mesenchymal markers (epithelial/mesenchymal cells). These epithelial/mesenchymal cells are the only xenograft-derived cells that can be cultured and with passaging undergo EMT and differentiate into mesenchymal cells. Our study provides a venue for improved virotherapy of cancer as well as new insights into cancer cell biology.
| S-EPMC2738419 | biostudies-literature
Project description:ObjectiveEarly detection and treatment are particularly important to epithelial ovarian cancer (EOC). Studies have shown that circular RNA (circRNA) dysregulation is associated with the proliferation and metastasis of ovarian cancer cells. This study focused on the role of serum exosomal circular forkhead box protein P1 (circFoxp1) on survival outcome and cisplatin (DDP) resistance in patients with EOC.MethodsQuantitative polymerase chain reaction, 5-ethynyl-2'-deoxyuridine (EdU) staining, CCK-8, luciferase reporter assay, RNA immunoprecipitation, tumor xenograft in nude mice, and bioinformatic analysis were performed.ResultsCirculating exosomal circFoxp1 was significantly increased in patients with EOC, especially in DDP-resistant EOC patients. circFoxp1 expression was positively associated with International Federation of Gynecology and Obstetrics stage, primary tumor size, lymphatic metastasis, distant metastasis, residual tumor diameter, and clinical response. Exosomal circFoxp1 also was an independent factor predicting survival and disease recurrence in patients with EOC. Overexpression of circFoxp1 could promote cell proliferation and confer DDP resistance, while knockdown of circFoxp1 could inhibit cell proliferation and enhance DDP sensitivity in vitro and in vivo. In addition, miR-22 and miR-150-3p mimic treatment attenuated circFoxp1-meadiated DDP resistance, while miR-22 and miR-150-3p inhibitor treatment enhanced DDP resistance that mitigated by circFoxp1 knockdown. Furthermore, circFoxp1 positively regulated the expression of CCAAT enhancer binding protein gamma (CEBPG) and formin like 3 (FMNL3) through miR-22 and miR-150-3p.ConclusionscircFoxp1 is an oncogene in EOC cells and can confer DDP resistance to EOC cells. Circulating exosomal circFoxp1 can be used as a biomarker and potential therapeutic target for EOC.
| S-EPMC7440976 | biostudies-literature
Project description:Semaphorin-7a (SEMA7A), best known as a neuroimmune molecule, plays a diverse role in many cellular processes and pathologies. Here, we show that SEMA7A promotes anoikis resistance in cultured mammary epithelial cells through integrins and activation of pro-survival kinase AKT, which led us to investigate a role for SEMA7A during postpartum mammary gland involution-a normal developmental process where cells die by anoikis. Our results reveal that SEMA7A is expressed on live mammary epithelial cells during involution, that SEMA7A expression is primarily observed in α6-integrin expressing cells, and that luminal progenitor cells, specifically, are decreased in mammary glands of SEMA7A-/- mice during involution. We further identify a SEMA7A-α6/β1-integrin dependent mechanism of mammosphere formation and chemoresistance in mammary epithelial cells and suggest that this mechanism is relevant for recurrence in breast cancer patients.
| S-EPMC8463677 | biostudies-literature
Project description:Ductal carcinoma in situ (DCIS) is characterized by ductal epithelial cells that have filled the luminal space of the breast duct and survive despite loss of extracellular matrix contact. In normal epithelial cells, the loss of such contact triggers a form of apoptosis known as detachment-induced apoptosis or "anoikis." TMS1/ASC is a bipartite adaptor molecule that participates in inflammatory and apoptotic signaling pathways. Epigenetic silencing of TMS1 has been observed in a significant proportion of human breast and other cancers, but the mechanism by which TMS1 silencing contributes to carcinogenesis is unknown. Here, we examined the role of TMS1 in anoikis. We found that TMS1 expression is induced in response to loss of substratum interactions in breast epithelial cells. siRNA-mediated knockdown of TMS1 leads to anoikis resistance, due in part to the persistent activation of extracellular signal-regulated kinase and an impaired ability to up-regulate the BH3-only protein Bim. We further show that the detachment-induced cleavage of procaspase-8, a newly described mediator of cellular adhesion, is significantly inhibited in the absence of TMS1. These data show a novel upstream role for TMS1 in the promotion of anoikis, and suggest that silencing of TMS1 may contribute to the pathogenesis of breast cancer by allowing epithelial cells to bypass cell death in the early stages of breast cancer development. This conclusion is supported by in vivo data showing that TMS1 is selectively down-regulated in the aberrant epithelial cells filling the lumen of the breast duct in a subset of primary DCIS lesions.
| S-EPMC2837082 | biostudies-other
Project description:The mucin 1 (MUC1) heterodimeric oncoprotein is overexpressed in human prostate cancers with aggressive pathologic and clinical features. However, few insights are available regarding the functional role of MUC1 in prostate cancer.Effects of MUC1-C on androgen receptor (AR) expression were determined by RT-PCR, immunoblotting and AR promoter activation. Coimmunoprecipitations, direct binding assays, and chromatin immunoprecipitation (ChIP) studies were performed to assess the interaction between MUC1-C and AR. Cells were analyzed for invasion, growth in androgen-depleted medium, and sensitivity to MUC1-C inhibitors.The present studies in androgen-dependent LNCaP and LAPC4 prostate cancer cells demonstrate that the oncogenic MUC1-C subunit suppresses AR expression. The results show that MUC1-C activates a posttranscriptional mechanism involving miR-135b-mediated downregulation of AR mRNA levels. The results further demonstrate that MUC1-C forms a complex with AR through a direct interaction between the MUC1-C cytoplasmic domain and the AR DNA-binding domain (DBD). In addition, MUC1-C associates with AR in a complex that occupies the PSA promoter. The interaction between MUC1-C and AR is associated with induction of the epithelial-mesenchymal transition (EMT) and increased invasion. MUC1-C also conferred growth in androgen-depleted medium and resistance to bicalutamide treatment. Moreover, expression of MUC1-C resulted in sensitivity to the MUC1-C inhibitor GO-203 with inhibition of growth in vitro. GO-203 treatment also inhibited growth of established tumor xenografts in nude mice.These findings indicate that MUC1-C suppresses AR expression in prostate cancer cells and confers a more aggressive androgen-independent phenotype that is sensitive to MUC1-C inhibition.
| S-EPMC3413781 | biostudies-literature
Project description:Here, we set out to test the novel hypothesis that increased mitochondrial biogenesis in epithelial cancer cells would "fuel" enhanced tumor growth. For this purpose, we generated MDA-MB-231 cells (a triple-negative human breast cancer cell line) overexpressing PGC-1? and MitoNEET, which are established molecules that drive mitochondrial biogenesis and increased mitochondrial oxidative phosphorylation (OXPHOS). Interestingly, both PGC-1? and MitoNEET increased the abundance of OXPHOS protein complexes, conferred autophagy resistance under conditions of starvation and increased tumor growth by up to ~3-fold. However, this increase in tumor growth was independent of neo-angiogenesis, as assessed by immunostaining and quantitation of vessel density using CD31 antibodies. Quantitatively similar increases in tumor growth were also observed by overexpression of PGC-1? and POLRMT in MDA-MB-231 cells, which are also responsible for mediating increased mitochondrial biogenesis. Thus, we propose that increased mitochondrial "power" in epithelial cancer cells oncogenically promotes tumor growth by conferring autophagy resistance. As such, PGC-1?, PGC-1?, mitoNEET and POLRMT should all be considered as tumor promoters or "metabolic oncogenes." Our results are consistent with numerous previous clinical studies showing that metformin (a weak mitochondrial "poison") prevents the onset of nearly all types of human cancers in diabetic patients. Therefore, metformin (a complex I inhibitor) and other mitochondrial inhibitors should be developed as novel anticancer therapies, targeting mitochondrial metabolism in cancer cells.
| S-EPMC3524213 | biostudies-literature
Project description:Non-small cell lung cancers (NSCLCs) that harbor an oncogenic KRAS mutation are often associated with resistance to targeted therapies. The MUC1-C transmembrane protein is aberrantly overexpressed in NSCLCs and confers a poor outcome; however, the functional role for MUC1-C in mutant KRAS NSCLC cells has remained unclear. The present studies demonstrate that silencing MUC1-C in A549/KRAS(G12S) and H460/KRAS(Q61H) NSCLC cells is associated with downregulation of AKT signaling and inhibition of growth. Overexpression of a MUC1-C(CQC?AQA) mutant, which inhibits MUC1-C homodimerization and function, suppressed both AKT and MEK activation. Moreover, treatment with GO-203, an inhibitor of MUC1-C homodimerization, blocked AKT and MEK signaling and decreased cell survival. The results further demonstrate that targeting MUC1-C suppresses expression of the ZEB1 transcriptional repressor by an AKT-mediated mechanism, and in turn induces miR-200c. In concert with these effects on the ZEB1/miR-200c regulatory loop, targeting MUC1-C was associated with reversal of the epithelial-mesenchymal transition (EMT) and inhibition of self-renewal capacity. Loss of MUC1-C function also attenuated KRAS independence and inhibited growth of KRAS mutant NSCLC cells as tumors in mice. These findings support a model in which targeting MUC1-C inhibits mutant KRAS signaling in NSCLC cells and thereby reverses the EMT phenotype and decreases self-renewal.
| S-EPMC4253405 | biostudies-literature
Project description:BackgroundAnoikis resistance plays a critical role in the tumor metastasis by allowing survival of cancer cells in the systemic circulation. We previously showed that long non-coding RNAs APOC1P1-3 (lncRNA APOC1P1-3) inhibit apoptosis of breast cancer cells. In this study, we explored its role in anoikis resistance.MethodsWe induced anoikis resistance in two breast cancer cell lines (MCF-7 and MDA-MB-231) under anchorage-independent culture conditions and studied lncRNA APOC1P1-3 effects on apoptosis. Using Dual-Luciferase activity assay, we determined whether it specifically binds to miRNA-188-3P. We further explored its role in lung metastasis by injecting MDA-MB-231 and MDA-MB-231-APOC1P1-3-knock-down cells in female BALB/c nude mice.ResultsWe found that lncRNA APOC1P1-3 suppressed early apoptosis of these cells (demonstrated by gain or loss of their function, respectively) and promoted anoikis resistance via reducing activated- Caspase 3, 8, 9 and PARP. Moreover, it specifically binds to the target miRNA-188-3p acting as a "sponge" to block the inhibition of Bcl-2 (an anti-apoptosis protein).ConclusionsOur study supports a theory that lncRNA APOC1P1-3 can promote development of breast cancer metastasis via anoikis resistance by specifically binding to miRNA-188-3p to block the inhibition of Bcl-2.
| S-EPMC8074441 | biostudies-literature
Project description:Multiple inositol polyphosphate phosphatase (Mipp), a highly conserved but poorly understood histidine phosphatase, dephosphorylates higher-order IPs (IP4-IP6) to IP3. To gain insight into the biological roles of these enzymes, we have characterized Drosophila mipp1. mipp1 is dynamically expressed in the embryonic trachea, specifically in the leading cells of migrating branches at late stages, where Mipp1 localizes to the plasma membrane and filopodia. FGF signaling activates mipp1 expression in these cells, where extensive filopodia form to drive migration and elongation by cell intercalation. We show that Mipp1 facilitates formation and/or stabilization of filopodia in leading cells through its extracellular activity. mipp1 loss decreases filopodia number, whereas mipp1 overexpression increases filopodia number in a phosphatase-activity-dependent manner. Importantly, expression of Mipp1 gives cells a migratory advantage for the lead position in elongating tracheal branches. Altogether, these findings suggest that extracellular pools of inositol polyphosphates affect cell behavior during development.
| S-EPMC4776642 | biostudies-literature