The mRNA-binding Protein TTP/ZFP36 in Hepatocarcinogenesis and Hepatocellular Carcinoma

Abstract

Hepatic lipid deposition and inflammation represent risk factors for hepatocellular carcinoma (HCC). The mRNA-binding protein tristetraprolin (TTP, gene name ZFP36) has been suggested as a tumor suppressor in several malignancies, but it increases insulin resistance. The aim of this study was to elucidate the role of TTP in hepatocarcinogenesis and HCC progression. Employing liver-specific TTP-knockout (lsTtp-KO) mice in the diethylnitrosamine (DEN) hepatocarcinogenesis model, we observed a significantly reduced tumor burden compared to wild-type animals. Upon short-term DEN treatment, modelling early inflammatory processes in hepatocarcinogenesis, lsTtp-KO mice exhibited a reduced monocyte/macrophage ratio as compared to wild-type mice. While short-term DEN strongly induced an abundance of saturated and poly-unsaturated hepatic fatty acids, lsTtp-KO mice did not show these changes. These findings suggested anti-carcinogenic actions of TTP deletion due to effects on inflammation and metabolism. Interestingly, though, investigating effects of TTP on different hallmarks of cancer suggested tumor-suppressing actions: TTP inhibited proliferation, attenuated migration, and slightly increased chemosensitivity. In line with a tumor-suppressing activity, we observed a reduced expression of several oncogenes in TTP-overexpressing cells. Accordingly, ZFP36 expression was downregulated in tumor tissues in three large human data sets. Taken together, this study suggests that hepatocytic TTP promotes hepatocarcinogenesis, while it shows tumor-suppressive actions during hepatic tumor progression.

ZFP36 Binds With PRC1 to Inhibit Tumor Growth and Increase 5-Fu Chemosensitivity of Hepatocellular Carcinoma

“…These authors suggested that ZFP36 downregulation is inversely correlated to the Wnt/β-catenin pathway, which is constitutively activated in CRC, and that there is a loss of posttranscriptional regulatory circuits during tumor development and progression. Coincidently, a recent study also found that overexpressed ZFP36 could decrease EMT and colony formation in vitro , and promote chemosensitivity to doxorubicin or sorafenib (Krohler et al, 2019 ), which further suggested the positive role of ZFP36 in upregulating chemosensitivity of HCC cells. Our work indicated that PRC1 expression is controlled by ZFP36 through ARE-mediated post-translational regulation.…”

“…Several publications have demonstrated that ZFP36 is linked to cancer thanks to evidence showing its down-regulated state in several tumors (Sanduja et al, 2012 ; Griseri and Pages, 2014 ; Montorsi et al, 2016 ). Interestingly, a very recent paper discovered that ZFP36 deletion could exert anti-tumorigenicity actions due to effects on inflammation and metabolism in a diethylnitrosamine (DEN) hepatocarcinogenesis model (Krohler et al, 2019 ). But during hepatic tumor progression, ZFP36 acted as tumor-suppressor by inhibiting cell proliferation and migration, and slightly increasing chemosensitivity to doxorubicin and sorafénib (Krohler et al, 2019 ).…”

“…Interestingly, a very recent paper discovered that ZFP36 deletion could exert anti-tumorigenicity actions due to effects on inflammation and metabolism in a diethylnitrosamine (DEN) hepatocarcinogenesis model (Krohler et al, 2019 ). But during hepatic tumor progression, ZFP36 acted as tumor-suppressor by inhibiting cell proliferation and migration, and slightly increasing chemosensitivity to doxorubicin and sorafénib (Krohler et al, 2019 ). However, the underlying molecular mechanism by which ZFP36 inhibits tumor growth in HCC progression remains unclear.…”

The Tristetraprolin Family of RNA-Binding Proteins in Cancer: Progress and Future Prospects

“…NOTCH1 Thymocyte-specific ZFP36L1 and ZFP36L2 deficient mice develop T cell acute lymphoblastic leukemia by upregulating Notch 1 [8]. TTP is downregulated in HCC tumors and hepatic TTP has a tumor suppressive role during tumor progression [54].…”

“…TTP is significantly downregulated in liver tumors. During tumor progression, TTP functions as a tumor suppressor and inhibits proliferation and migration, reduces expression of several oncogenes, and increases chemo sensitivity [54]. The anti-proliferative properties of metformin, an anti-diabetic drug, in breast cancer cells were mediated by induction of TTP through c-Myc downregulation [28].…”