PARG suppresses tumorigenesis and downregulates genes controlling angiogenesis, inflammatory response, and immune cell recruitment

Abstract

Chemokines are highly expressed in tumor microenvironment and play a critical role in all aspects of tumorigenesis, including the recruitment of tumor-promoting immune cells, activation of cancer-associated fibroblasts, angiogenesis, metastasis, and growth. Poly (ADP-ribose) polymerase (PARP) is a multi-target transcription regulator with high levels of poly(ADP-ribose) (pADPr) being reported in a variety of cancers. Furthermore, poly (ADP-ribose) glycohydrolase (PARG), an enzyme that degrades pADPr, has been reported to be downregulated in tumor tissues with abnormally high levels of pADPr. In conjunction to this, we have recently reported that the reduction of pADPr, by either pharmacological inhibition of PARP or PARG’s overexpression, disrupts renal carcinoma cell malignancy in vitro. Here, we use 3 T3 mouse embryonic fibroblasts, a universal model for malignant transformation, to follow the effect of PARG upregulation on cells’ tumorigenicity in vivo. We found that the overexpression of PARG in mouse allografts produces significantly smaller tumors with a delay in tumor onset. As downregulation of PARG has also been implicated in promoting the activation of pro-inflammatory genes, we also followed the gene expression profile of PARG-overexpressing 3 T3 cells using RNA-seq approach and observed that chemokine transcripts are significantly reduced in those cells. Our data suggest that the upregulation of PARG may be potentially useful for the tumor growth inhibition in cancer treatment and as anti-inflammatory intervention.

Assessment of tumor microenvironment in gastric adenocarcinoma

“…Although many of the biochemical messengers secreted by CAFs were shown to be involved in tumor progression, there are also studies that showed CAFs can have an inhibitory effect on tumor progression [ 28 , 29 , 30 ]. Genetic studies clearly demonstrated that CAFs are heterogeneous and synthesize several types of molecules with different effects on the carcinogenesis process.…”

Disrupting Poly(ADP-ribosyl)ating Pathway Creates Premalignant Conditions in Mammalian Liver

“…Moreover, it has been established that PARP proteins are often upregulated, resulting in increased pADPr levels in numerous malignant tumors [33][34][35][36][37]. Decreasing pADPr levels through PARG overexpression has been shown to mitigate the malignant behavior of cancer cells and reduce cancer growth [38][39][40]. PARP1, the most abundant PARP protein in mammalian cells and the principal producer of pADPr, plays a pivotal role in hepatocyte function and has been implicated in the development of liver diseases [41][42][43].…”