Knockout of Putative Tumor Suppressor Aldh1l1 in Mice Reprograms Metabolism to Accelerate Growth of Tumors in a Diethylnitrosamine (DEN) Model of Liver Carcinogenesis

Krupenko, Natalia I.; Sharma, Jaspreet; Fogle, Halle M.; Pediaditakis, Peter; Strickland, Kyle C.; Du, Xiuxia; Helke, Kristi L.; Sumner, Susan; Krupenko, Sergey A.

doi:10.3390/cancers13133219

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Knockout of Putative Tumor Suppressor Aldh1l1 in Mice Reprograms Metabolism to Accelerate Growth of Tumors in a Diethylnitrosamine (DEN) Model of Liver Carcinogenesis

^1,2,†,

^2,†

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^2,‡,

³,

⁴,

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^1,2 and

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Department of Nutrition, University of North Carolina, Chapel Hill, NC 27599, USA

Nutrition Research Institute, University of North Carolina, Kannapolis, NC 28081, USA

Department of Pathology, Duke University, Durham, NC 27708, USA

⁴

Department of Bioinformatics & Genomics, UNC Charlotte, Charlotte, NC 28223, USA

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Department of Comparative Medicine, Medical University of South Carolina, Charleston, SC 29425, USA

Author to whom correspondence should be addressed.

^†

Co-first authors.

^‡

Present address: LyGenesis, Inc. 2730 Sidney Street, Suite 300, Pittsburgh, PA 15203, USA.

Academic Editors: Donat Kögel and Nikolai Timchenko

Cancers 2021, 13(13), 3219; https://doi.org/10.3390/cancers13133219

Received: 27 May 2021 / Revised: 15 June 2021 / Accepted: 22 June 2021 / Published: 28 June 2021

(This article belongs to the Section Molecular Cancer Biology)

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Cancers 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.

Abstract

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. View Full-Text

Keywords: ALDH1L1; mouse knockout; folate metabolism; liver cancer; diethylnitrosamine (DEN) carcinogenesis; metabolomics

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MDPI and ACS Style

Krupenko, N.I.; Sharma, J.; Fogle, H.M.; Pediaditakis, P.; Strickland, K.C.; Du, X.; Helke, K.L.; Sumner, S.; Krupenko, S.A. Knockout of Putative Tumor Suppressor Aldh1l1 in Mice Reprograms Metabolism to Accelerate Growth of Tumors in a Diethylnitrosamine (DEN) Model of Liver Carcinogenesis. Cancers 2021, 13, 3219. https://doi.org/10.3390/cancers13133219

AMA Style

Krupenko NI, Sharma J, Fogle HM, Pediaditakis P, Strickland KC, Du X, Helke KL, Sumner S, Krupenko SA. Knockout of Putative Tumor Suppressor Aldh1l1 in Mice Reprograms Metabolism to Accelerate Growth of Tumors in a Diethylnitrosamine (DEN) Model of Liver Carcinogenesis. Cancers. 2021; 13(13):3219. https://doi.org/10.3390/cancers13133219

Chicago/Turabian Style

Krupenko, Natalia I., Jaspreet Sharma, Halle M. Fogle, Peter Pediaditakis, Kyle C. Strickland, Xiuxia Du, Kristi L. Helke, Susan Sumner, and Sergey A. Krupenko. 2021. "Knockout of Putative Tumor Suppressor Aldh1l1 in Mice Reprograms Metabolism to Accelerate Growth of Tumors in a Diethylnitrosamine (DEN) Model of Liver Carcinogenesis" Cancers 13, no. 13: 3219. https://doi.org/10.3390/cancers13133219

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Knockout of Putative Tumor Suppressor Aldh1l1 in Mice Reprograms Metabolism to Accelerate Growth of Tumors in a Diethylnitrosamine (DEN) Model of Liver Carcinogenesis

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