Forkhead box C1 promotes metastasis and invasion of non–small cell lung cancer by binding directly to the lysyl oxidase promoter

Abstract

Increasing evidence indicates that human forkhead box C1 (FOXC1) plays important roles in tumor development and metastasis. However, the underlying molecular mechanism of FOXC1 in non–small cell lung cancer (NSCLC) metastasis remains unclear. Here, we identified FOXC1 as an independent prognostic factor in NSCLC and showed clear biological implications in invasion and metastasis. FOXC1 overexpression enhanced the proliferation, migration and invasion of NSCLC cells, whereas FOXC1 silencing impaired the effects both in vitro and in vivo. Importantly, we found a positive correlation between FOXC1 expression and lysyl oxidase (LOX) expression in NSCLC cells and patient samples. Downregulation of LOX or LOX activity inhibition in NSCLC cells inhibited the FOXC1‐driven effects on cellular migration and invasion. Xenograft models showed that inhibition of LOX activity by β‐aminopropionitrile monofumarate decreased the number of lung metastases. Mechanistically, we demonstrated a novel FOXC1‐LOX mechanism that was involved in the invasion and metastasis of NSCLC. Dual‐luciferase assay and ChIP identified that FOXC1 bound directly in the LOX promoter region and activated its transcription. Collectively, the present study offered new insight into FOXC1 in the mediation of NSCLC metastasis through interaction with the LOX promoter and further revealed that targeted inhibition of LOX protein activity could prevent lung metastasis in murine xenograft models. These data implicated FOXC1 as a potential therapeutic strategy for the treatment of NSCLC metastasis.

Collagen Biosynthesis, Processing, and Maturation in Lung Ageing

“…LOX is synthesised as a pro-enzyme and activation requires removal of the pro-peptide, notably by the same enzymes that cleave off the C-terminal pro-peptide of type I collagen (BMP1/Tolloid-like proteinases) (71). The mature protein is overexpressed in various cancer types including lung adenocarcinoma, typically correlates with poor prognosis, and has been described to create a stiffer microenvironment which supports tumour growth and metastasis (222,(224)(225)(226)(227)(228)(229)(230). In contrast, the tumour-suppressing activities of LOX are attributed to the released pro-peptide (222,223,231,232).…”

The Role of the ECM in Lung Cancer Dormancy and Outgrowth

“…In non-pulmonary cancers, the lysyl oxidase family profoundly promotes the dissemination of cancer cells from the primary site as well as the colonization of and outgrowth at distant sites, including the lung, through direct effects on collagen architecture and tissue biomechanics (41,(139)(140)(141)(142)(143)(144), and through the recruitment of myeloid cells to the premetastatic niche (68). The secretion of lysyl oxidase (LOX) by tumor cells in response to intratumoral hypoxia, or as a wound healing response to surgery, can increase the systemic LOX activity, thereby catalyzing collagen crosslinking at distant sites, including within the lung (68, 145).…”

Insights into the New Cancer Therapy through Redox Homeostasis and Metabolic Shifts

“…Increased collagen cross-lining and ECM stiffness activates PI3K and extracellular-regulatory kinase (ERK) signaling pathways, and stimulates Neu-mediated oncogenic transformation [64]. Some studies suggest that LOX is essentially involved in cancer cell invasion and progression through ECM remodeling [65,66]. Therefore, the CME initiates tumorigenesis, promotes cancer cell proliferation, and induces metastasis by controlling angiogenesis, immune functions and the ECM components.…”