Stanniocalcin 1 promotes metastasis, lipid metabolism and cisplatin chemoresistance via the FOXC2/ITGB6 signaling axis in ovarian cancer

Lin, Feikai; Li, Xiaoduan; Wang, Xinjing; Sun, Huizhen; Wang, Ziliang; Wang, Xipeng

doi:10.1186/s13046-022-02315-3

Cited by 51 publications

(30 citation statements)

References 63 publications

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“…Furthermore, ANGPTL4 has been implicated in carboplatin resistance and hypoxia-induced anoikis resistance (40,41). STC1 is a glycoprotein that functions as a paracrine/autocrine factor involved in many physiological/pathological pathways that promote cancer cell viability, migration, proliferation, invasion and chemoresistance (47)(48)(49). STC1 is also secreted by multiple cell types in the tumor microenvironment, including cancer cells, cancer associated fibroblasts, macrophages and adipocytes (48,(50)(51)(52).…”

Section: Discussionmentioning

confidence: 99%

Cancer-associated mesothelial cell–derived ANGPTL4 and STC1 promote the early steps of ovarian cancer metastasis

Bajwa¹,

Kordylewicz²,

Bilecz³

et al. 2023

JCI Insight

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Ovarian cancer (OvCa) preferentially metastasizes in association with mesothelial cell-lined surfaces. We sought to determine if mesothelial cells are required for OvCa metastasis and detect alterations in mesothelial cell gene expression and cytokine secretion upon interaction with OvCa cells. Using omental samples from patients with high-grade serous OvCa and mouse models with Wt1-driven GFP-expressing mesothelial cells, we validated the intratumoral localization of mesothelial cells during human and mouse OvCa omental metastasis. Removing mesothelial cells ex vivo from human and mouse omenta or in vivo using diphtheria toxin mediated ablation in Msln-Cre mice, significantly inhibited OvCa cell adhesion and colonization. Human ascites induced angiopoietinlike 4 (ANGPTL4) and stanniocalcin 1 (STC1) expression and secretion by mesothelial cells. Inhibition of STC1 or ANGPTL4 via RNAi, obstructed OvCa cell-induced mesothelial cell to mesenchymal transition while inhibition of ANGPTL4 alone obstructed OvCa cell-induced mesothelial cell migration and glycolysis. Inhibition of mesothelial cell ANGPTL4 secretion via RNAi prevented mesothelial cell induced monocyte migration, endothelial cell vessel formation and OvCa cell adhesion, migration, and proliferation. In contrast, inhibition of mesothelial cell STC1 secretion via RNAi prevented mesothelial cell induced endothelial cell vessel formation and OvCa cell adhesion, migration, proliferation, and invasion. Additionally, blocking ANPTL4 function with antibodies reduced the ex vivo colonization of three different OvCa cell lines on human omental tissue explants and in vivo colonization of ID8 p53-/-Brca2-/cells on mouse omenta. These findings indicate that mesothelial cells are important to the initial stages of OvCa metastasis, and that the crosstalk between mesothelial cells and the tumor microenvironment, promotes OvCa metastasis through the secretion of ANGPTL4.

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Section: Discussionmentioning

confidence: 99%

Cancer-associated mesothelial cell–derived ANGPTL4 and STC1 promote the early steps of ovarian cancer metastasis

Bajwa¹,

Kordylewicz²,

Bilecz³

et al. 2023

JCI Insight

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“…High STC1 expression was associated with advanced tumor stage and poor PFS in CRC patients. STC1 could promote metastasis, lipid metabolism and cisplatin chemoresistance via directly binding to ITGB6 in ovarian cancer ( 41 ). We also found that the total expression of CES1 gradually increased as tumor invaded deeper although its expression is higher in normal tissues.…”

Section: Discussionmentioning

confidence: 99%

Spatially resolved transcriptomics revealed local invasion-related genes in colorectal cancer

Liu

Chen²,

Peng³

et al. 2023

Front. Oncol.

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ObjectiveLocal invasion is the first step of metastasis, the main cause of colorectal cancer (CRC)-related death. Recent studies have revealed extensive intertumoral and intratumoral heterogeneity. Here, we focused on revealing local invasion-related genes in CRC. MethodsWe used spatial transcriptomic techniques to study the process of local invasion in four CRC tissues. First, we compared the pre-cancerous, cancer center, and invasive margin in one section (S115) and used pseudo-time analysis to reveal the differentiation trajectories from cancer center to invasive margin. Next, we performed immunohistochemical staining for RPL5, STC1, AKR1B1, CD47, and HLA-A on CRC samples. Moreover, we knocked down AKR1B1 in CRC cell lines and performed CCK-8, wound healing, and transwell assays to assess cell proliferation, migration, and invasion.ResultsWe demonstrated that 13 genes were overexpressed in invasive clusters, among which the expression of CSTB and TM4SF1 was correlated with poor PFS in CRC patients. The ribosome pathway was increased, while the antigen processing and presentation pathway was decreased along CRC progression. RPL5 was upregulated, while HLA-A was downregulated along cancer invasion in CRC samples. Pseudo-time analysis revealed that STC1, AKR1B1, SIRPA, C4orf3, EDNRA, CES1, PRRX1, EMP1, PPIB, PLTP, SULF2, and EGFL6 were unpregulated along the trajectories. Immunohistochemic3al staining showed the expression of STC1, AKR1B1, and CD47 was increased along cancer invasion in CRC samples. Knockdown of AKR1B1 inhibited CRC cells’ proliferation, migration, and invasion.ConclusionsWe revealed the spatial heterogeneity within CRC tissues and uncovered some novel genes that were associated with CRC invasion.

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“…Similar results have also been reported in models of NSCLC and colorectal cancer, where AKT- and/or MAPK-dependent resistance to cisplatin, oxaliplatin, and 5-fluorouracil has been found to be mediated by FOXC2. 6 , 11 , 13 Though the mechanism(s) by which FOXC2 promotes MAPK signaling has yet to be elucidated, insight into FOXC2-dependent activation of PI3K-AKT signaling was recently provided by Lin et al, 34 who found that FOXC2 binds directly to the promoter of the STC1 gene encoding stanniocalcin 1, a glycoprotein that interacts with the integrin ITGB6 to stimulate PI3K signaling. Of note, silencing of either STC1 or ITGB6 expression in ovarian cancer cell lines increased their sensitivity to cisplatin, highlighting stanniocalcin 1 and ITGB6 as important intermediaries in a FOXC2-STC1-ITGB6-PI3K signaling axis that promotes cancer chemoresistance.…”

Section: Foxc2-associated Mechanisms Of Resistance To Chemotherapymentioning

confidence: 99%

The FOXC2 Transcription Factor: A Master Regulator of Chemoresistance in Cancer

Hargadon

Strong

2023

Technol Cancer Res Treat

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FOXC2, a member of the forkhead box family of transcription factors, is an emerging oncogene that has been linked to several hallmarks of cancer progression. Among its many oncogenic functions is the promotion of drug resistance, with evidence supporting roles for FOXC2 in escape from broad classes of chemotherapeutics across an array of cancer types. In this Mini-Review, we highlight the current understanding of the mechanisms by which FOXC2 drives cancer chemoresistance, including its roles in the promotion of epithelial-mesenchymal transition, induction of multidrug transporters, activation of the oxidative stress response, and deregulation of cell survival signaling pathways. We discuss the clinical implications of these findings, including strategies for modulating FOXC2-associated chemoresistance in cancer. Particular attention is given to ways in which FOXC2 and its downstream gene products and pathways can be targeted to restore chemosensitivity in cancer cells. In addition, the utility of FOXC2 expression as a predictor of patient response to chemotherapy is also highlighted, with emphasis on the value of FOXC2 as a novel biomarker that can be used to guide therapeutic choice towards regimens most likely to achieve clinical benefit during frontline therapy.

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Stanniocalcin 1 promotes metastasis, lipid metabolism and cisplatin chemoresistance via the FOXC2/ITGB6 signaling axis in ovarian cancer

Cited by 51 publications

References 63 publications

Cancer-associated mesothelial cell–derived ANGPTL4 and STC1 promote the early steps of ovarian cancer metastasis

Cancer-associated mesothelial cell–derived ANGPTL4 and STC1 promote the early steps of ovarian cancer metastasis

Spatially resolved transcriptomics revealed local invasion-related genes in colorectal cancer

The FOXC2 Transcription Factor: A Master Regulator of Chemoresistance in Cancer

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