Tristetraprolin Promotes Hepatic Inflammation and Tumor Initiation but Restrains Cancer Progression to Malignancy

Abstract

Background & Aims Tristetraprolin (TTP) is a key post-transcriptional regulator of inflammatory and oncogenic transcripts. Accordingly, TTP was reported to act as a tumor suppressor in specific cancers. Herein, we investigated how TTP contributes to the development of liver inflammation and fibrosis, which are key drivers of hepatocarcinogenesis, as well as to the onset and progression of hepatocellular carcinoma (HCC). Methods TTP expression was investigated in mouse/human models of hepatic metabolic diseases and cancer. The role of TTP in nonalcoholic steatohepatitis and HCC development was further examined through in vivo/vitro approaches using liver-specific TTP knockout mice and a panel of hepatic cancer cells. Results Our data demonstrate that TTP loss in vivo strongly restrains development of hepatic steatosis and inflammation/fibrosis in mice fed a methionine/choline-deficient diet, as well as HCC development induced by the carcinogen diethylnitrosamine. In contrast, low TTP expression fostered migration and invasion capacities of in vitro transformed hepatic cancer cells likely by unleashing expression of key oncogenes previously associated with these cancerous features. Consistent with these data, TTP was significantly down-regulated in high-grade human HCC, a feature further correlating with poor clinical prognosis . Finally, we uncover hepatocyte nuclear factor 4 alpha and early growth response 1, two key transcription factors lost with hepatocyte dedifferentiation, as key regulators of TTP expression. Conclusions Although TTP importantly contributes to hepatic inflammation and cancer initiation, its loss with hepatocyte dedifferentiation fosters cancer cells migration and invasion. Loss of TTP may represent a clinically relevant biomarker of high-grade HCC associated with poor prognosis.

Mir-21 Suppression Promotes Mouse Hepatocarcinogenesis

“…We previously reported such discrepant results for another important post-transcriptional regulator, which acts similarly to a miRNA, i.e., the RNA-binding protein tristetraprolin (TTP). In vivo studies using TTP knockout mice indicated an oncogenic function for this protein in HCC development, whereas TTP appeared to have a tumor-suppressive role in hepatic cultured cancer cells [ 90 ].…”

The Emerging Role of Stress Granules in Hepatocellular Carcinoma

“…Indeed, suppression of TTP phosphorylation by MK2 inhibitor was shown to impair TTP activity in HCC cell lines [130], whereas TTP ability to regulate c-Myc was abrogated by methylation of a single CpG site in its promoter [131]. We also recently showed that the TTP expression is regulated by the HNF4α/EGR1 axis in Huh7 cells [125]. Although the precise role and functions of TTP in liver diseases and HCC have started to be delineated, whether TTP regulates SGs biogenesis or requires these entities for its functions, as suggested in non-hepatic cell lines [127], remains to be investigated in the liver.…”

“…eIF4E2) -GYF2 (GRB10-interacting GYF protein 2) cap-binding complex, and a Not-1 binding domain [120][121][122]. It is usually described as a tumor suppressor, downregulated in many human cancers, and its level correlates with a poor clinical outcome [123][124][125]. TTP binds to mRNA transcripts and targets them for degradation in P-bodies.…”

“…In the liver, we recently showed that TTP promotes the development of nonalcoholic steatohepatitis (NASH), a condition from which HCC can develop [5]. In human HCC, TTP is downregulated at the protein level, and we could show using transgenic mouse models that TTP displays a dual oncogenic and tumor-suppressive role depending on the stage of the disease [125,128]. TTP overexpression was further shown by others to prevent activation of LX2 stellate cells suggesting that TTP may also restrain hepatic fibrosis development depending on the cell context and environment [129].…”

Tristetraprolin, a Potential Safeguard Against Carcinoma: Role in the Tumor Microenvironment

“…Besides, lower level of TTP is related to more aggressive phenotype in HCC. Loss of TTP will show high correlation with late-stage, high-grade of HCC (23,24). Therefore, TTP could be considered a tumor suppressor in most cancers, and upregulating TTP expression might help improve prognosis.…”