Phospholipase D2 promotes disease progression of renal cell carcinoma through the induction of angiogenin

Abstract

A hallmark of clear cell renal cell carcinoma (ccRCC) is the presence of intracellular lipid droplets (LD) and it is assumed that phosphatidic acid (PA) produced by phospholipase D (PLD) plays some role in the LD formation. However, little is known about the significance of PLD in ccRCC. In this study, we examined the expression levels of PLD in ccRCC. The classical mammalian isoforms of PLD are PLD1 and PLD2, and the levels of both mRNA were higher at the primary tumor sites than in normal kidney tissues. Similarly, both PLD were significantly abundant in tumor cells as determined by analysis using immunohistochemical staining. Importantly, a higher level of PLD was significantly associated with a higher tumor stage and grade. Because PLD2 knockdown effectively suppressed the cell proliferation and invasion of ccRCC as compared with PLD1 in vitro, we examined the effect of PLD2 in vivo. Notably, shRNA‐mediated knockdown of PLD2 suppressed the growth and invasion of tumors in nude mouse xenograft models. Moreover, the higher expression of PLD2 was significantly associated with poorer prognosis in 67 patients. As for genes relating to the tumor invasion of PLD2, we found that angiogenin (ANG) was positively regulated by PLD2. In fact, the expression levels of ANG were elevated in tumor tissues as compared with normal kidney and the inhibition of ANG activity with a neutralizing antibody significantly suppressed tumor invasion. Overall, we revealed for the first time that PLD2‐produced PA promoted cell invasion through the expression of ANG in ccRCC cells.

Reprogramming of Metabolism in Kidney Cancer

“…[17][18][19]57 The level of PLD2 is increased in ccRCC compared with normal kidney and is correlated with stage, grade, and poor prognosis. 67 Although an in vitro study showed that PLD2 increases HIF-1a and HIF-2a at a translational level, 68 it is not clear if the effect of PLD2 on HIFs is mediated through LPA and its GPCRs. As an inhibitor of ATX prolongs sensitivity to sunitinib, 64 these findings suggest that LPA is a potential therapeutic target for RCC.…”

Phospholipase D2 in prostate cancer: protein expression changes with Gleason score

“…Many studies now implicate phospholipase D (PLD) in tumorigenesis since total PLD activity and the expression of its two major isoforms PLD1 and PLD2 are elevated in many cancers where increases can correlate with prognosis. 1 – 8 Higher PLD activity is also linked to survival and migration signals in human breast cancer cells and in androgen-insensitive prostate cancer cell lines. 9 , 10 Selective inhibition of PLD1 or PLD2 also makes breast cancer cells more sensitive to radiation.…”

Effect of simulated microgravity on metabolism of HGC‑27 gastric cancer cells

“…MT1-MMP, tethered to the plasma membrane, is a key protein associated with the migration of cancer cells (67). PLD2 generates small lipid molecules, such as phosphatidic acid, which can regulate the movement of the cytoskeleton, proliferation and migration (68)(69)(70). Therefore, it has been suggested that PLD2 and its small lipid molecules can regulate MT1-MMP for invasion and metastasis.…”