The interferon-inducible protein viperin controls cancer metabolic reprogramming to enhance cancer progression
Kyung Mi Choi, Jeong Jin Kim, Jihye Yoo, Ku Sul Kim, Youngeun Gu, John Eom, Haengdueng Jeong, Kyungeun Kim, Ki Taek Nam, Young Soo Park, Joon-Yong Chung, Jun-Young Seo
Kyung Mi Choi, Jeong Jin Kim, Jihye Yoo, Ku Sul Kim, Youngeun Gu, John Eom, Haengdueng Jeong, Kyungeun Kim, Ki Taek Nam, Young Soo Park, Joon-Yong Chung, Jun-Young Seo
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Research Article Metabolism Oncology

The interferon-inducible protein viperin controls cancer metabolic reprogramming to enhance cancer progression

Abstract

Metabolic reprogramming is an important cancer hallmark. However, the mechanisms driving metabolic phenotypes of cancer cells are unclear. Here, we show that the interferon-inducible (IFN-inducible) protein viperin drove metabolic alteration in cancer cells. Viperin expression was observed in various types of cancer and was inversely correlated with the survival rates of patients with gastric, lung, breast, renal, pancreatic, or brain cancer. By generating viperin knockdown or stably expressing cancer cells, we showed that viperin, but not a mutant lacking its iron-sulfur cluster–binding motif, increased lipogenesis and glycolysis via inhibition of fatty acid β-oxidation in cancer cells. In the tumor microenvironment, deficiency of fatty acids and oxygen as well as production of IFNs upregulated viperin expression via the PI3K/AKT/mTOR/HIF-1α and JAK/STAT pathways. Moreover, viperin was primarily expressed in cancer stem-like cells (CSCs) and functioned to promote metabolic reprogramming and enhance CSC properties, thereby facilitating tumor growth in xenograft mouse models. Collectively, our data indicate that viperin-mediated metabolic alteration drives the metabolic phenotype and progression of cancer.

Authors

Kyung Mi Choi, Jeong Jin Kim, Jihye Yoo, Ku Sul Kim, Youngeun Gu, John Eom, Haengdueng Jeong, Kyungeun Kim, Ki Taek Nam, Young Soo Park, Joon-Yong Chung, Jun-Young Seo

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Figure 6

Viperin drives the metabolic phenotype and cancer progression in vivo.

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Viperin drives the metabolic phenotype and cancer progression in vivo. (...
(A and B) Tumor growth in the MKN28 control and viperin-KD cell–derived xenograft mouse models. (A) Spheroids of the stable cell lines were dissociated and counted. A single-cell suspension was mixed with an equal volume of Matrigel. The mixture (1 × 104 cells/mouse) was injected subcutaneously into the flanks of 6-week-old male nude mice (n = 8/cell line). Tumor growth was monitored weekly, and the tumor volume was measured using a metric caliper. (B) After 10 weeks, mice were sacrificed, and tumors were isolated. Tumor size and weight were measured. Data are presented as the mean ± SEM (n = 8). (C and D) IHC staining for viperin (C) and immunofluorescence staining for viperin and CD44 (D) in tumors isolated from the stable cell–derived xenograft mouse models. Tissue sections were stained with specific mAbs against CD44, a CSC marker, and viperin. Nuclei were stained with DAPI (blue). Scale bars: 100 μm. (E) Expression of viperin and CD44 in the isolated tumors. Each protein was detected by immunoblotting using specific mAbs. β-Actin was used as a loading control. (F) Lipogenesis in the isolated tumors. Relative mRNA levels of the indicated genes in tumors were measured by qRT-PCR and normalized to ACTB mRNA. Data are presented as the mean ± SEM (n = 4 in triplicate). **P < 0.01 and ***P < 0.001, by 1-way ANOVA with Dunnett’s multiple-comparison test (A, B, and F).