Mitochondrial pyruvate carrier modulates the epithelial-mesenchymal transition in cholangiocarcinoma

Ohashi,Tomofumi; Eguchi,Hidetoshi; Kawamoto,Koichi; Konno,Masamitsu; Asai,Ayumu; Colvin,Hugh; Ueda,Yuji; Takaoka,Hirofumi; Iwagami,Yoshifumi; Yamada,Daisaku; Asaoka,Tadafumi; Noda,Takehiro; Wada,Hiroshi; Gotoh,Kunihito; Kobayashi,Shogo; Koseki,Jun; Satoh,Taroh; Ogawa,Kazuhiko; Doki,Yuichiro; Mori,Masaki; Ishii,Hideshi

doi:10.3892/or.2017.6172

March-2018 Volume 39 Issue 3

Full Size Image

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

An International Open Access Journal Devoted to General Medicine.

March-2018 Volume 39 Issue 3

Full Size Image

Article

Mitochondrial pyruvate carrier modulates the epithelial-mesenchymal transition in cholangiocarcinoma

Authors:
- Tomofumi Ohashi
- Hidetoshi Eguchi
- Koichi Kawamoto
- Masamitsu Konno
- Ayumu Asai
- Hugh Colvin
- Yuji Ueda
- Hirofumi Takaoka
- Yoshifumi Iwagami
- Daisaku Yamada
- Tadafumi Asaoka
- Takehiro Noda
- Hiroshi Wada
- Kunihito Gotoh
- Shogo Kobayashi
- Jun Koseki
- Taroh Satoh
- Kazuhiko Ogawa
- Yuichiro Doki
- Masaki Mori
- Hideshi Ishii
View Affiliations / Copyright

Affiliations: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan, Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan, Department of Radiation Oncology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan, Department of Medical Data Science, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
Pages: 1276-1282
|
Published online on: December 20, 2017

https://doi.org/10.3892/or.2017.6172
Expand metrics +

Abstract

Intrahepatic cholangiocarcinoma (ICC) is known to have a high malignant potential. Because of its high recurrence rate, ICC has a poor prognosis even after complete tumor resection. Compared with normal differentiated cells, cancer cells have an altered metabolism for supporting their survival in severe conditions. Cancer cells acquire additional malignant potential as a result of this metabolic alteration. Thus, the molecules known to be involved in cancer metabolism, could be novel therapeutic targets. The mitochondrial pyruvate carrier (MPC) is a recently discovered pyruvate transporter, which is located in the mitochondrial inner membrane. Although MPC is composed of two subunits, it has been reported that the MPC1 subunit is specifically associated with poor prognosis in several cancers, including colorectal and prostate cancer. However, only a few studies have assessed the clinical significance of MPC1 and the molecular mechanisms underlying its influence on cancer progression are not well understood. This study aimed to clarify the function of MPC1 that affects the malignant potential of ICC. The expression of MPC1 in ICC clinical specimens was determined by immunohistochemistry. In addition, the correlations between MPC1 expression and the survival rate, as well as various clinicopathological parameters were assessed. Low MPC1 expression correlated with poor ICC prognosis and was correlated with tumor invasion and distant metastasis. Both these phenomena are closely associated with the epithelial-mesenchymal transition (EMT). Therefore, we investigated the impact of altering the MPC1 gene expression on the malignant potential of cancer cells using biliary tract cancer cell lines in vitro. The expression of MPC1 was downregulated in the cells induced to undergo EMT following treatment with TGF-β. Furthermore, the inhibition of MPC1 expression induced EMT in cancer cells, and the overexpression of MPC1 suppressed the migration of tumor cells. These results indicated that MPC1 could be a novel therapeutic target in some cancers.

View Figures

View References

1	Kobayashi S, Igami T, Ebata T, Yokoyama Y, Sugawara G, Mizuno T, Nimura Y and Nagino M: Long-term survival following extended hepatectomy with concomitant resection of all major hepatic veins for intrahepatic cholangiocarcinoma: Report of a case. Surg Today. 45:1058–1063. 2015. View Article : Google Scholar : PubMed/NCBI
2	Mizuno T, Ebata T, Yokoyama Y, Igami T, Sugawara G, Yamaguchi J and Nagino M: Adjuvant gemcitabine monotherapy for resectable perihilar cholangiocarcinoma with lymph node involvement: A propensity score matching analysis. Surg Today. 47:182–192. 2017. View Article : Google Scholar : PubMed/NCBI
3	Wellner UF, Shen Y, Keck T, Jin W and Xu Z: The survival outcome and prognostic factors for distal cholangiocarcinoma following surgical resection: A meta-analysis for the 5-year survival. Surg Today. 47:271–279. 2017. View Article : Google Scholar : PubMed/NCBI
4	Ebata T, Ercolani G, Alvaro D, Ribero D, Di Tommaso L and Valle JW: Current status on cholangiocarcinoma and gallbladder cancer. Liver Cancer. 6:59–65. 2016. View Article : Google Scholar : PubMed/NCBI
5	Kroemer G and Pouyssegur J: Tumor cell metabolism: Cancer's Achilles' heel. Cancer Cell. 13:472–482. 2008. View Article : Google Scholar : PubMed/NCBI
6	Pavlova NN and Thompson CB: The emerging hallmarks of cancer metabolism. Cell Metab. 23:27–47. 2016. View Article : Google Scholar : PubMed/NCBI
7	Zhao Y, Butler EB and Tan M: Targeting cellular metabolism to improve cancer therapeutics. Cell Death Dis. 4:e5322013. View Article : Google Scholar : PubMed/NCBI
8	Liberti MV and Locasale JW: The Warburg Effect: How does it benefit cancer cells? Trends Biochem Sci. 41:211–218. 2016. View Article : Google Scholar : PubMed/NCBI
9	Vander Heiden MG, Cantley LC and Thompson CB: Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 324:1029–1033. 2009. View Article : Google Scholar : PubMed/NCBI
10	Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, Royer RE, Vander Jagt DL, Semenza GL and Dang CV: Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci USA. 107:pp. 2037–2042. 2010; View Article : Google Scholar : PubMed/NCBI
11	Hamabe A, Konno M, Tanuma N, Shima H, Tsunekuni K, Kawamoto K, Nishida N, Koseki J, Mimori K, Gotoh N, et al: Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial-mesenchymal transition. Proc Natl Acad Sci USA. 111:pp. 15526–15531. 2014; View Article : Google Scholar : PubMed/NCBI
12	Bricker DK, Taylor EB, Schell JC, Orsak T, Boutron A, Chen YC, Cox JE, Cardon CM, Van Vranken JG, Dephoure N, et al: A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science. 337:96–100. 2012. View Article : Google Scholar : PubMed/NCBI
13	Herzig S, Raemy E, Montessuit S, Veuthey JL, Zamboni N, Westermann B, Kunji ER and Martinou JC: Identification and functional expression of the mitochondrial pyruvate carrier. Science. 337:93–96. 2012. View Article : Google Scholar : PubMed/NCBI
14	Patterson JN, Cousteils K, Lou JW, Manning Fox JE, MacDonald PE and Joseph JW: Mitochondrial metabolism of pyruvate is essential for regulating glucose-stimulated insulin secretion. J Biol Chem. 289:13335–13346. 2014. View Article : Google Scholar : PubMed/NCBI
15	Vanderperre B, Bender T, Kunji ER and Martinou JC: Mitochondrial pyruvate import and its effects on homeostasis. Curr Opin Cell Biol. 33:35–41. 2015. View Article : Google Scholar : PubMed/NCBI
16	Schell JC, Olson KA, Jiang L, Hawkins AJ, Van Vranken JG, Xie J, Egnatchik RA, Earl EG, DeBerardinis RJ and Rutter J: A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. Mol Cell. 56:400–413. 2014. View Article : Google Scholar : PubMed/NCBI
17	Wang L, Xu M, Qin J, Lin SC, Lee HJ, Tsai SY and Tsai MJ: MPC1, a key gene in cancer metabolism, is regulated by COUPTFII in human prostate cancer. Oncotarget. 7:14673–14683. 2016.PubMed/NCBI
18	Li X, Ji Y, Han G, Li X, Fan Z, Li Y, Zhong Y, Cao J, Zhao J, Zhang M, et al: MPC1 and MPC2 expressions are associated with favorable clinical outcomes in prostate cancer. BMC Cancer. 16:8942016. View Article : Google Scholar : PubMed/NCBI
19	Zhao QJ, Yu YB, Zuo XL, Dong YY and Li YQ: Milk fat globule-epidermal growth factor 8 is decreased in intestinal epithelium of ulcerative colitis patients and thereby causes increased apoptosis and impaired wound healing. Mol Med. 18:497–506. 2012. View Article : Google Scholar : PubMed/NCBI
20	Xu J, Lamouille S and Derynck R: TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 19:156–172. 2009. View Article : Google Scholar : PubMed/NCBI
21	Dong C, Yuan T, Wu Y, Wang Y, Fan TW, Miriyala S, Lin Y, Yao J, Shi J, Kang T, et al: Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell. 23:316–331. 2013. View Article : Google Scholar : PubMed/NCBI

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Mitochondrial pyruvate carrier modulates the epithelial-mesenchymal transition in cholangiocarcinoma

This article is mentioned in:

Abstract

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Related Articles