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Volume 13
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10.3390/cancers13020348
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Article

Discovery of Functional Alternatively Spliced PKM Transcripts in Human Cancers

by
Xiangyu Li
1,†,
Woonghee Kim
1,†,
Muhammad Arif
1,
Chunxia Gao
2,
Andreas Hober
1,
David Kotol
1,
Linnéa Strandberg
1,
Björn Forsström
1,
Åsa Sivertsson
1,
Per Oksvold
1,
Hasan Turkez
3,
Morten Grøtli
2,
Yusuke Sato
4,5,
Haruki Kume
5,
Seishi Ogawa
4,6,
Jan Boren
7,
Jens Nielsen
8,9,
Mathias Uhlen
1,
Cheng Zhang
1,10,* and
Adil Mardinoglu
1,11,*
1
Science for Life Laboratory, KTH—Royal Institute of Technology, SE-17165 Stockholm, Sweden
2
Department of Chemistry and Molecular Biology, University of Gothenburg, SE-41296 Gothenburg, Sweden
3
Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum 25240, Turkey
4
Department of Pathology and Tumor Biology, Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto 606-8501, Japan
5
Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan
6
Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, SE-17177 Stockholm, Sweden
7
Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, SE-41345 Gothenburg, Sweden
8
Department of Biology and Biological Engineering, Chalmers University of Technology, SE-41296 Gothenburg, Sweden
9
BioInnovation Institute, DK-2200 Copenhagen N, Denmark
10
Key Laboratory of Advanced Drug Preparation Technologies, School of Pharmaceutical Sciences, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China
11
Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London SE1 9RT, UK
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this paper.
Cancers 2021, 13(2), 348; https://doi.org/10.3390/cancers13020348
Received: 28 December 2020 / Revised: 15 January 2021 / Accepted: 17 January 2021 / Published: 19 January 2021
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Simple Summary

Pyruvate kinase muscle type (PKM) is a key enzyme in glycolysis and is a mediator of the Warburg effect in tumors. The association of PKM with survival of cancer patients is controversial. In this study, we investigated the associations of the alternatively spliced transcripts of PKM with cancer patients’ survival outcomes and explained the conflicts in previous studies. We discovered three poorly studied alternatively spliced PKM transcripts that exhibited opposite prognostic indications in different human cancers based on integrative systems analysis. We also detected their protein products and explored their potential biological functions based on in-vitro experiments. Our analysis demonstrated that alternatively spliced transcripts of not only PKM but also other genes should be considered in cancer studies, since it may enable the discovery and targeting of the right protein product for development of the efficient treatment strategies.

Abstract

Pyruvate kinase muscle type (PKM) is a key enzyme in glycolysis and plays an important oncological role in cancer. However, the association of PKM expression and the survival outcome of patients with different cancers is controversial. We employed systems biology methods to reveal prognostic value and potential biological functions of PKM transcripts in different human cancers. Protein products of transcripts were shown and detected by western blot and mass spectrometry analysis. We focused on different transcripts of PKM and investigated the associations between their mRNA expression and the clinical survival of the patients in 25 different cancers. We find that the transcripts encoding PKM2 and three previously unstudied transcripts, namely ENST00000389093, ENST00000568883, and ENST00000561609, exhibited opposite prognostic indications in different cancers. Moreover, we validated the prognostic effect of these transcripts in an independent kidney cancer cohort. Finally, we revealed that ENST00000389093 and ENST00000568883 possess pyruvate kinase enzymatic activity and may have functional roles in metabolism, cell invasion, and hypoxia response in cancer cells. Our study provided a potential explanation to the controversial prognostic indication of PKM, and could invoke future studies focusing on revealing the biological and oncological roles of these alternative spliced variants of PKM. View Full-Text
Keywords: alternative splicing; cancer; PKM; transcriptomics alternative splicing; cancer; PKM; transcriptomics
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MDPI and ACS Style

Li, X.; Kim, W.; Arif, M.; Gao, C.; Hober, A.; Kotol, D.; Strandberg, L.; Forsström, B.; Sivertsson, Å.; Oksvold, P.; Turkez, H.; Grøtli, M.; Sato, Y.; Kume, H.; Ogawa, S.; Boren, J.; Nielsen, J.; Uhlen, M.; Zhang, C.; Mardinoglu, A. Discovery of Functional Alternatively Spliced PKM Transcripts in Human Cancers. Cancers 2021, 13, 348. https://doi.org/10.3390/cancers13020348

AMA Style

Li X, Kim W, Arif M, Gao C, Hober A, Kotol D, Strandberg L, Forsström B, Sivertsson Å, Oksvold P, Turkez H, Grøtli M, Sato Y, Kume H, Ogawa S, Boren J, Nielsen J, Uhlen M, Zhang C, Mardinoglu A. Discovery of Functional Alternatively Spliced PKM Transcripts in Human Cancers. Cancers. 2021; 13(2):348. https://doi.org/10.3390/cancers13020348

Chicago/Turabian Style

Li, Xiangyu; Kim, Woonghee; Arif, Muhammad; Gao, Chunxia; Hober, Andreas; Kotol, David; Strandberg, Linnéa; Forsström, Björn; Sivertsson, Åsa; Oksvold, Per; Turkez, Hasan; Grøtli, Morten; Sato, Yusuke; Kume, Haruki; Ogawa, Seishi; Boren, Jan; Nielsen, Jens; Uhlen, Mathias; Zhang, Cheng; Mardinoglu, Adil. 2021. "Discovery of Functional Alternatively Spliced PKM Transcripts in Human Cancers" Cancers 13, no. 2: 348. https://doi.org/10.3390/cancers13020348

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