Abstract
Simple SummaryCancers often loose the enzyme of folate metabolism ALDH1L1. We proposed that such loss is advantageous for the malignant tumor growth and tested this hypothesis in mice proficient or deficient (gene knockout) in ALDH1L1 expression. Liver cancer in both groups was induced by injection of chemical carcinogen diethylnitrosamine. While the number of tumors observed in ALDH1L1 proficient and deficient mice was similar, tumors grew faster and to a larger size in the knockout mice. We conclude that the ALDH1L1 loss promotes liver tumor growth without affecting tumor initiation or multiplicity. Accelerated growth of tumors lacking the enzyme was linked to several metabolic pathways, which are beneficial for rapid proliferation.Cytosolic 10-formyltetrahydrofolate dehydrogenase (ALDH1L1) is commonly downregulated in human cancers through promoter methylation. We proposed that ALDH1L1 loss promotes malignant tumor growth. Here, we investigated the effect of the Aldh1l1 mouse knockout (Aldh1l1−/−) on hepatocellular carcinoma using a chemical carcinogenesis model. Fifteen-day-old male Aldh1l1 knockout mice and their wild-type littermate controls (Aldh1l1+/+) were injected intraperitoneally with 20 μg/g body weight of DEN (diethylnitrosamine). Mice were sacrificed 10, 20, 28, and 36 weeks post-DEN injection, and livers were examined for tumor multiplicity and size. We observed that while tumor multiplicity did not differ between Aldh1l1−/− and Aldh1l1+/+ animals, larger tumors grew in Aldh1l1−/− compared to Aldh1l1+/+ mice at 28 and 36 weeks. Profound differences between Aldh1l1−/− and Aldh1l1+/+ mice in the expression of inflammation-related genes were seen at 10 and 20 weeks. Of note, large tumors from wild-type mice showed a strong decrease of ALDH1L1 protein at 36 weeks. Metabolomic analysis of liver tissues at 20 weeks showed stronger differences in Aldh1l1+/+ versus Aldh1l1−/− metabotypes than at 10 weeks, which underscores metabolic pathways that respond to DEN in an ALDH1L1-dependent manner. Our study indicates that Aldh1l1 knockout promoted liver tumor growth without affecting tumor initiation or multiplicity.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, with a high mortality rate [1,2]
Tumor suppressor, could be expected itsenhances loss enhances tumorigenesis. Investigated this putative function of the protein by comparing malignant tumor growth in. We investigated this putative function of the protein by comparing malignant tumor wild-type and Aldh1l1 knockout mice using the DEN model of liver carcinogenesis
While the ALDH1L1 protein is commonly lost in malignant human tumors, it is not clear whether the lack of corresponding enzymatic activity can promote tumorigenesis
Summary
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, with a high mortality rate [1,2]. To develop targeted therapeutic strategies, a more thorough understanding of the genetic alterations and metabolic derangements of HCC is needed To this end, numerous studies have evaluated the gene expression profile of HCCs (reviewed in [4,5,6,7]). Another study highlighted the downregulation of ALDH1L1 as a part of a gene signature for late-stage compared to early-stage HCCs as well as for highgrade compared to low-grade cancers [9]. In line with these findings, it was reported that the decreased expression of ALDH1L1 was associated with poor prognosis in HCC [10]
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