PO-280 Hypoxia-induced PLD2 promotes tumorigenesis and stem cell-like properties in tumour cells

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Introduction Phospholipase D (PLD) hydrolyzes phosphatidylcholine, the most abundant phospholipid in eukaryotic cell membranes, and it is overexpressed in a wide variety of cancers. In solid tumours, PLD2 has been associated to hypoxic regions and it has been purposed to mediate postranslational regulation of HIF-α, but its contribution to protein stabilisation or degradation is not clear. Moreover, hypoxia has a key role in tumour population heterogeneity and cancer stem cells increase and it has also been associated with increased malignancy, poor prognosis and resistance to radiotherapy and chemotherapy. Material and methods To characterise the implication of PLD2 in tumorigenesis and the increase of stem cell-like properties under hypoxia conditions, we generated two PLD2 knock-down colon cancer cell lines from HCT116 and LS180 commercial cell lines. We also generated PLD2 lipase mutant cell lines. We checked PLD2 protein and mRNA levels under normoxia and hypoxia conditions, as well as tumorigenesis, using different approaches in vitro: growth curves, colony formation assays, percentage of holoclones and capacity to generate tumorspheres. In addition, we analysed several stem cell markers by FACS analysis and RT-qPCR. Results and discussions We first show that the increase of PLD2 under hypoxia conditions depends on its lipase activity. Hypoxia-induced PLD2 increases cell growth and anchorage-independent cell growth. Additionally, we show that hypoxia-induced PLD2 increases the stem cell-like properties of cancer cells, including clonogenicity and the capacity to form tumorspheres. Conclusion Altogether, our results demonstrate that hypoxia-induced PLD2 increases tumorigenesis and stem cell-like properties in colon cancer cells.

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