Absence of Malat1 does not prevent DEN-induced hepatocarcinoma in mice

Abstract

Long non-coding RNAs (lncRNA) are key regulators of gene expression both at the transcriptional and post-transcriptional levels. The lncRNA metastasis associated lung adenocarcinoma transcript 1 (Malat1) is overexpressed in many types of cancer, including hepatocarcinoma, and induces cell proliferation in several cell lines in vitro. However, the direct causal effects of Malat1 on hepatocyte proliferation and liver carcinogenesis in vivo are not fully understood. To better determine the contribution of Malat1 to hepatocarcinoma oncogenesis, this study was aimed at testing the hypothesis that its absence confers resistance to the development of liver tumors. Male Malat1-/- mice and their wild-type (WT) littermates were studied one year after treatment with the genotoxic agent diethylnitrosamine (DEN), a potent inducer of liver cancer. As expected, in WT mice, Malat1 expression was significantly higher in hepatic tumors than in healthy liver regions. Altered hepatic mRNA levels of Ki67, HDAC3, NFκB and p27 were observed in DEN-treated Malat1-/- mice. Despite this, these mice were characterized by similar liver weight, prevalence of tumors, and histological features compared to those of their WT littermates. In parallel, plasma lipids and glucose homeostasis did not significantly differ between DEN-treated groups. These findings support a role for Malat1 as a marker of liver carcinogenesis, but also suggest that its role in the regulation of hepatocyte hyperproliferation in mice is either minimal or masked by redundant and/or overwhelming mechanisms.

Loss of Malat1 does not modify age- or diet-induced adipose tissue accretion and insulin resistance in mice

“…To assess the physiological relevance of a reduction in Malat1 upon aging, we first documented age-associated changes in energy balance in Malat1 +/+ and Malat1 -/- littermates. Consistent with expected gene knockout in other tissues [ 16 ], Malat1 transcripts were barely detectable in either vWAT or scWAT of Malat1 -/- mice ( S3 Fig ). As reported, at a young age, male and female Malat1 -/- mice had a body weight similar to their Malat1 +/+ counterparts ( Fig 2A ).…”

“…Male ob/ob , and db/db mice, as well as their wild-type counterparts, were from The Jackson Laboratory (Bar Harbor, ME, USA). The generation of Malat1 +/+ and Malat1 -/- mice on a pure C57BL/6J genetic background has been described previously [ 16 ]. In a first study, Malat1 +/+ and Malat1 -/- littermates were fed ad libitum with regular chow (Harlan NIH31) until sacrifice.…”

“…More recently, it was shown to promote lipid accumulation in hepatocytes by altering SREBP-1c stability [ 15 ]. Yet, Malat1 -deficient mice develop normally and show no overt phenotype, as demonstrated by four independent groups [ 16 – 20 ].…”

Hypoxia-induced long non-coding RNA Malat1 is dispensable for renal ischemia/reperfusion-injury

“…Malat1 was shown to impact on proliferation of cardiomyocytes in vitro 30 . However, in the in vivo studies referenced above changes between wildtype and Malat1 knockout animals were not detected 24 , 25 . Taking into account these in vitro and biomarkers studies as well as our results of increased expression levels in hypoxic cells and blood of patients, we believe, that Malat1 may have a role as a biomarker of different pathologies, including AKI.…”

“…In contrast to the aforementioned studies the absence of Malat1 does not seem to impact on the resolution of disease. In a study involving genotoxic stress using diethylnitrosamine (DEN) to induce liver cancer Malat1 knockout mice and littermate controls were investigated 24 . Here, Malat1 knockout mice did not differ with respect to tumor development after 1 year compared to controls.…”