Mint3-mediated L1CAM expression in fibroblasts promotes cancer cell proliferation via integrin α5β1 and tumour growth

Abstract

Fibroblasts are some of the major cells in tumour tissues that influence tumour progression and drug resistance. However, our understanding on fibroblast-mediated tumour malignancy remains incomplete. Munc18-1-interacting protein 3 (Mint3) is known as an activator of hypoxia-inducible factor-1 (HIF-1) even during normoxia in cancer cells, macrophages and fibroblasts. Although Mint3 promotes ATP production via glycolysis by activating HIF-1 in cancer cells and macrophages, the biological role of Mint3-mediated HIF-1 activation in fibroblasts remains unclear. To address this, we examined whether Mint3 in fibroblasts contributes to tumour growth. Mint3 depletion in mouse embryonic fibroblasts (MEFs) decreased tumour growth of co-injected human breast cancer cells, MDA-MB-231 and epidermoid carcinoma A431 cells in mice. In MEFs, Mint3 also promoted cancer cell proliferation in vitro in a cell–cell contact-dependent manner. Mint3-mediated cancer cell proliferation depended on HIF-1, and further gene expression analysis revealed that the cell adhesion molecule, L1 cell adhesion molecule (L1CAM), was induced by Mint3 and HIF-1 in fibroblasts. Mint3-mediated L1CAM expression in fibroblasts stimulated the ERK signalling pathway via integrin α5β1 in cancer cells, and promoted cancer cell proliferation in vitro and tumour growth. In cancer-associated fibroblasts (CAFs), knockdown of MT1-MMP, which promotes Mint3-mediated HIF-1 activation, or Mint3 decreased L1CAM expression. As MEFs, CAFs also promoted cancer cell proliferation in vitro, and tumour growth via Mint3 and L1CAM. In human breast cancer specimens, the number of fibroblasts expressing L1CAM, Mint3 and MT1-MMP was higher in cancer regions than in adjacent benign regions. In addition, more phospho-ERK1/2-positive cancer cells existed in the peripheral region surrounded by the stroma than in the central region of solid breast cancer nest. Thus, Mint3 in fibroblasts might be a good target for cancer therapy by regulating cancer cell-stromal cell communication.

Fallopian tube precursor lesions of serous ovarian carcinoma require L1CAM for dissemination and metastasis

“…Correspondingly, we observed a reduced activity in both pathways in the OVCAR8-L1 cells (Supplementary Figure 3B), which is also in agreement with previous reports (Gast et al 2005;Doberstein et al 2011;Nakaoka et al 2017). Furthermore, siRNA-mediated attenuation of fibronectin or integrin-ɑ5 expression abrogated the activation of ERK and AKT in the fallopian tube cell lines, while it decreased AKT but not ERK activation in OVCAR8 cells ( Figure 6F).…”

Development of an Immune-Related Prognostic Signature in Breast Cancer

“…L1CAM, an axonal glycoprotein belonging to immunoglobulin superfamily, is associated with poor prognosis and metastases formation in several cancers, including breast and pancreas. Over-expression of L1CAM not only induced NF-kB activation but also mediated the phosphorylation of FAK and Src, which promoted cancer cell proliferation and tumor growth (Kiefel et al, 2012;Nakaoka et al, 2017). LCN2 is a neutrophil gelatinase-associated lipocalin and plays a role in innate immunity by limiting bacterial growth.…”

Mint3 depletion restricts tumor malignancy of pancreatic cancer cells by decreasing SKP2 expression via HIF-1

“…In pancreatic cancer cells, Mint3 depletion did not affect HIF-1α protein levels, and HIF-1α depletion also did not affect Mint3 expression. Inflammatory cytokines such as TNF-α can induce Mint3 expression in cancer-associated fibroblasts [42]. Moreover, NF-κB signaling promotes HIF-1α expression [43].…”