Stanniocalcin 1 promotes metastasis by enhancing lipid metabolism via FOXC2/ITGB6 signaling axis in ovarian cancer
Ontology highlight
ABSTRACT: Stanniocalcin 1 (STC1) plays an integral role in the metastasis of ovarian cancer. However, the functional role of STC1 in lipid metabolism is not fully understood. Single-cell sequencing assays verified that STC1 expression was significantly enhanced in ovarian cancer tissues compared with para-carcinoma tissues, and it was further up-regulated in peritoneal metastasis tissues compared with tumor tissues. In vitro and in vivo experiments demonstrated that STC1 promoted cell proliferation and metastasis by enhancing lipid metabolism. Mechanistically, STC1 directly bound to integrin β6 (ITGB6) and activated the PI3K signaling pathway. Moreover, STC1 was directly regulated by FOXC2 and FOXC2 was up-regulated and positively correlated with STC1 in ovarian cancer. Notably, STC1 knockdown had a synergistic effect with cisplatin (DDP) chemotherapy.Overall, these findings reveal that STC1 increases metastasis by promoting lipid metabolism via the FOXC2/ITGB6 signaling axis and may be a potential target for chemotherapy-resistant ovarian cancer.
Project description:Investigation of whole genome gene expression level changes in a colorectal cancer cell line SW480 expressing FOXC2, compared to the pBabe control cells. Genes associated with metastasis regulated by FOXC2 in colorectal cancer were analysed. The role of FOXC2 in breast cancer metastasis are further described in Mani SA, Yang J et al. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. PNAS 2007; 104: 10069-10074 . A six chip study using total RNA recovered from three separate cultures of SW480/pBabe and three separate cultures of SW480/FOXC2. Each chip measures the expression level of 45033 genes from SW480/pBabe or SW480/FOXC2.
Project description:Investigation of whole genome gene expression level changes in a colorectal cancer cell line SW480 expressing FOXC2, compared to the pBabe control cells. Genes associated with metastasis regulated by FOXC2 in colorectal cancer were analysed. The role of FOXC2 in breast cancer metastasis are further described in Mani SA, Yang J et al. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. PNAS 2007; 104: 10069-10074 .
Project description:Analysis of genes regulated by STC1 down-regulation in mouse 4T1 derived clone, 4T1ch9. STC1 expression is associated with tumor growth and metastasis. This study looks at genes affected when STC1 expression is down-regulated by STC1 shRNA.
Project description:Analysis of genes regulated by STC1 down-regulation in mouse 4T1 derived clone, 4T1ch9. STC1 expression is associated with tumor growth and metastasis. This study looks at genes affected when STC1 expression is down-regulated by STC1 shRNA. Total RNA isolated from shRNA transduced cells subjected to puromycin selection for 5-6 days.
Project description:Ovarian cancer is the most frequent cause of cancer death in women and the leading cause of death related to gynecological cancer, accounting for 5% of estimated cancer deaths. Due to its asymptomatic nature at early stages, most ovarian cancers were diagnosed at an advanced stage, with distant metastasis in the abdominal cavity. Cancer metastasis is the primary cause of morbidity, and contributes to 95% of cancer-related deaths. Metastatic ovarian cancer is closely related with recurrence and drug resistance, rendering metastasis as the major challenge in the course of ovarian cancer treatment. Thorough understanding of ovarian cancer metastasis is believed to contribute to improve cancer cure rates, while it is still not well elucidated. One important aspect of ovarian cancer metastasis research is the identification of driver molecular. To identify proteins required for ovarian cancer metastasis, we carried out unbiased high-throughput screening by comparing the expression profile of ovarian cancer primary and metastasis tissues.
Project description:Ovarian cancer is the most lethal gynecological malignancy and is characterized by peritoneal disseminated metastasis. Although O-mannosyltransferase TMTC1 is highly expressed by ovarian cancer, its pathophysiologic role in ovarian cancer remains unclear. Here, immunohistochemistry showed that TMTC1 was overexpressed in ovarian cancer tissues compared with the adjacent non-tumor ovarian tissues and high TMTC1 expression was associated with poor prognosis in patients with ovarian cancer. Silencing TMTC1 reduced ovarian cancer cell viability, migration, and invasion in vitro as well as suppressed peritoneal tumor growth and metastasis in vivo. Moreover, TMTC1 knockdown reduced cell-laminin adhesion, which was associated with the decreased phosphorylation of FAK at pY397. Conversely, TMTC1 overexpression promoted these malignant properties in ovarian cancer cells. Glycoproteomic analysis and Concanavalin A (ConA) pull-down assays showed that integrins β1 and β4 were novel O-mannosylated protein substrates of TMTC1. Furthermore, TMTC1-mediated cell migration and invasion were significantly reversed by siRNA-mediated knockdown of integrin β1 or β4. Collectively, these results suggest that TMTC1-mediated invasive behaviors are primarily through integrins β1 and β4 and that TMTC1 is a potential therapeutic target for ovarian cancer.
Project description:CCCTC-binding factor (CTCF) is an 11 zinc fingers transcription factor that functions as both an oncogenic and tumor suppressor, depending on the cancer types, through epigenetic regulation. Epigenetic regulation including DNA methylation and histone modifications are critically involved in cancer metastasis. We then hypothesized that CTCF might play a vital role in epithelial ovarian cancer metastasis. Firstly, we found that CTCF expression was elevated in ovarian cancer tissues compared to non-tumor tissues. The elevated expression of CTCF predicts poor prognosis of ovarian cancer patients. Then, we revealed that CTCF knockdown significantly inhibited the migration, invasion and metastasis of ovarian cancer cells, although it had no effect on cell proliferation and tumor growth, which have been demonstrated with both in vitro and in vivo experiments. More importantly, we observed a higher CTCF expression in metastatic lesions than that in primary lesions from ovarian cancer patients. Mechanically, PCR array demonstrated that CTCF might regulate a series of metastasis associated genes, including CTBP1, SERPINE1 and SRC. Finally, we observed positive correlations between CTCF expression and those three genes in epithelial ovarian cancer specimens. In conclusion, this study demonstrates that CTCF is an oncogene in ovarian cancer to promote tumor metastasis through broadly controlling the expression of metastasis-associated genes. Our findings suggest CTCF could be a novel drug target to treat ovarian cancer by interfering with cancer cell metastasis.
Project description:Macrophages form a primary immune cells population in tumor tissues and malignant ascites microenvironment (MAM). They can be activated and polarized into tumor-associated macrophages (TAM) by the embedded environment and promote tumor progression and metastasis However, the molecular mechanisms of MAM in macrophage polarization and the effects on epithelial ovarian cancer (EOC) metastatic progression remain elusive. Here, we found that that MAM modulates RhoA-GTPase-F-actin-Hippo signaling cascade in facilitating M2-like macrophage polarization that, in turn, promotes tumor dissemination. PUFA enriched magligant ascites microenvironment promote macrophage lipid oxidative phosphorylation and supression RhoA-GTPase-Yap1 axis. Genetic ablation Yap1 in macrophage exhibited M2-like polarization and enhanced ovrian tumor dissemination. Pharmacology inhibit Mst1/2 could rescue M2-like TAM polarization in MAM and alter the lipid oxidation of macrophages in MAM, more importantly, inhibit ovarian metastatic properties. Through comparasion primary TAM (P-TAM) and metastasis TAM (M-TAM), we proved that Hippo-Yap1 siganl results M-TAM with high M2/M1 ratio. These findings implicate critical functions of PUFA modulate RhoA-Hippo axis in facility TAM polarization and also suggest manipulation of PUFA metabolism or RhoA-Hippo siganl as a therapeutic strategy aganist EOC metastasis.