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PFKP is highly expressed in lung cancer and regulates glucose metabolism

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Abstract

Purpose

Although it has been reported that up-regulation of phosphofructokinase (PFK) expression is a major feature of malignant tumors, the role of platelet type PFK (PFKP) in tumor initiation and progression is as yet poorly understood. The objective of this study was to evaluate PFKP expression in lung cancer and its effect on glycolysis, and to explore correlations between PFKP expression levels and clinical lung cancer patient features.

Methods

PFKP mRNA expression levels in cancer tissues and adjacent normal tissues were compared using The Cancer Genome Atlas (TCGA) database. PFKP mRNA and protein expression levels in fresh lung cancer tissues and cell lines were assessed using quantitative real-time PCR and Western blotting. Immunohistochemistry (IHC) was used to assess PFKP expression in 150 archival lung adenocarcinoma samples, after which follow-up data and their correlations with clinical features and patient prognosis were evaluated. A retroviral shRNA-mediated method was used to construct stable cell lines expressing low levels of PFKP. Glucose, lactate and adenosine triphosphate concentrations in the cell culture supernatants were determined using enzymatic, spectrophotometric and enzyme-linked immunosorbent (ELISA) assays, respectively. The effect of PFKP expression on the proliferation of lung cancer cells was assessed using colony forming, MTT and flow cytometry assays, respectively. Finally, data from tissue samples of 533 patients with lung adenocarcinoma and 502 patients with lung squamous cell carcinoma were downloaded from the TCGA database, after which pathway and gene correlation information was retrieved using gene set enrichment analyses.

Results

We found that PFKP was highly expressed in lung cancer tissues and cell lines. Using IHC we found that PFKP was highly expressed in primary lung adenocarcinoma tissues and that a high expression was associated with a poor prognosis. Clinical data analysis revealed that the PFKP expression levels correlated with tumor size and patient survival. Lung cancer cell lines with decreased PFKP expression levels showed significant decreases in glucose uptake rates, lactate levels and adenosine triphosphate concentrations. They also exhibited significantly decreased proliferation rates, colony forming abilities and increased G2/M cell cycle phase percentages. Gene set enrichment analysis revealed that multiple pathways, including glycolytic pathways, may be involved in the regulation PFKP.

Conclusions

Our data indicate that PFKP is highly expressed in lung cancer tissues and cell lines and is associated with tumor size and patient prognosis. As such, PFKP may serve as a prognostic biomarker. We also found that PFKP regulates the level of glycolysis in lung cancer cells and is associated with lung cancer cell proliferation. These data may be instrumental for the design of new lung cancer treatment options.

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Abbreviations

IHC:

Immunohistochemistry

DMEM:

Dulbecco’s Modified Eagle’s Medium

FBS:

Fetal Bovine Serum;

qRT-PCR:

Quantitative Reverse Transcriptase PCR

NSCLC:

Non-Small Cell Lung Carcinoma

PFK-1:

Phosphofructokinase-1

ELISA:

Enzyme-Linked Immunosorbent Assay

TCGA:

The Cancer Genome Atlas

GSEA:

Gene Set Enrichment Analysis

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Acknowledgements

The authors thank Taizhou Hospital of Zhejiang Province for providing the research environment.

Availability of data and materials

All data generated or analyzed in this study are included in this published article.

Funding

This study was funded by Zhejiang Provincial Natural Fund (grant number LQ18H160029 and Y19H160116).

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Author notes

  1. Jianfei Shen, Zixian Jin and Haiyan Lv contributed equally to this work.

Authors and Affiliations

  1. Department of Thoracic Surgery, Taizhou Hospital of Zhejiang Province, Whenzhou Medical University, Linhai, 317000, China

    Jianfei Shen, Zixian Jin, Haiyan Lv, Ke Jin, Chengchu Zhu & Baofu Chen

  2. Whenzhou Medical University, Whenzhou, 325000, China

    Kangberee Jonas

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  1. Jianfei Shen
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  2. Zixian Jin
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Contributions

JF, ZJ, & HL searched the literature and drafted and revised the manuscript. KJ & KBJ processed the data. CZ and BC revised and approved the final manuscript.

Corresponding authors

Correspondence to Chengchu Zhu or Baofu Chen.

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The experimental protocol was established according to the ethical guidelines of the Helsinki Declaration, which was approved by the Medical Ethics Committee of Taizhou Hospital, Zhejiang Province, China. Written informed consent to participate in the study was obtained from all individual participants or their guardians.

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Written informed consent for publication was obtained from all participants.

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The authors declare that they have no competing interests.

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Shen, J., Jin, Z., Lv, H. et al. PFKP is highly expressed in lung cancer and regulates glucose metabolism. Cell Oncol. 43, 617–629 (2020). https://doi.org/10.1007/s13402-020-00508-6

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