FABP4 as a key determinant of metastatic potential of ovarian cancer

Abstract

The standard treatment for high-grade serous ovarian cancer is primary debulking surgery followed by chemotherapy. The extent of metastasis and invasive potential of lesions can influence the outcome of these primary surgeries. Here, we explored the underlying mechanisms that could increase metastatic potential in ovarian cancer. We discovered that FABP4 (fatty acid binding protein) can substantially increase the metastatic potential of cancer cells. We also found that miR-409-3p regulates FABP4 in ovarian cancer cells and that hypoxia decreases miR-409-3p levels. Treatment with DOPC nanoliposomes containing either miR-409-3p mimic or FABP4 siRNA inhibited tumor progression in mouse models. With RPPA and metabolite arrays, we found that FABP4 regulates pathways associated with metastasis and affects metabolic pathways in ovarian cancer cells. Collectively, these findings demonstrate that FABP4 is functionally responsible for aggressive patterns of disease that likely contribute to poor prognosis in ovarian cancer.

Reprogramming of fatty acid metabolism in cancer

“…For instance, FABP4 is a transcriptional target of HIF1α that facilitates extracellular scavenging of long-chain unsaturated lysophospholipids, including LPCs, lysophosphatidylethanolamines (LPEs) and lysophosphatidylglycerols (LPGs) that can be used as a nutrient source under conditions of metabolic stress. 27,28 Interestingly, this phenotype of increased FA scavenging is also recapitulated under normoxic conditions following oncogenic Ras activation, and is accompanied by reduced oxygen consumption, elevated citrate synthesis from reductive carboxylation and a consequent independence from SCD-1 to derive unsaturated FAs. 27 Taken together, these results demonstrate that whilst changes in the microenvironment conditions or oncogenic activation of signalling pathways confer resistance to SCD-1 inhibitors, they might open novel opportunities for therapy by increasing the reliance of cancer cells on FA uptake.…”

Adipocyte and lipid metabolism in cancer drug resistance

“…Increase of circulating levels of fatty acidbinding proteins. Recent findings show that adipose fatty acid-binding protein (A-FABP) and FABP4 promote cancer development and metastasis, partly through the mechanism of TAM activation (90,91). Circulating A-FABP is elevated in obese patients with breast cancer (92).…”

The Construction and Analysis of the Aberrant lncRNA-miRNA-mRNA Network in Adipose Tissue from Type 2 Diabetes Individuals with Obesity

“…Moreover, the association between each probe for the DElncRNA and each available miRNA was assessed by using the maximal information coefficient (MIC) computed by minerva, an R package [36,37]. The lncRNA-miRNA interactions were screened for the significance level set at MIC > 0:2 [38]. The mRNA-miRNA interactions were predicted by miRWalk 2.0 (http://www.umm.uni-heidelberg.de/apps/ zmf/mirwalk/), which incorporates 12 algorithms for prediction (TargetScan, RNAhybrid, RNA22, PITA, PicTar2, miR-Walk, Microt4, miRNAMap, miRDB, mirBridge, miRanda, and miRMap) [39].…”