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Pten-NOLC1 fusion promotes cancers involving MET and EGFR signalings

Oncogene volume 40, pages 1064–1076 (2021)Cite this article

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Abstract

Inactivation of Pten gene through deletions and mutations leading to excessive pro-growth signaling pathway activations frequently occurs in cancers. Here, we report a Pten derived pro-cancer growth gene fusion Pten-NOLC1 originated from a chr10 genome rearrangement and identified through a transcriptome sequencing analysis of human cancers. Pten-NOLC1 fusion is present in primary human cancer samples and cancer cell lines from different organs. The product of Pten-NOLC1 is a nuclear protein that interacts and activates promoters of EGFR, c-MET, and their signaling molecules. Pten-NOLC1 promotes cancer proliferation, growth, invasion, and metastasis, and reduces the survival of animals xenografted with Pten-NOLC1-expressing cancer cells. Genomic disruption of Pten-NOLC1 induces cancer cell death, while genomic integration of this fusion gene into the liver coupled with somatic Pten deletion produces spontaneous liver cancers in mice. Our studies indicate that Pten-NOLC1 gene fusion is a driver for human cancers.

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Fig. 1: Pten-NOLC1 fusion.
Fig. 2: Pten-NOLC1 fusion in human cancers.
Fig. 3: Pten-NOLC1 is localized in the nucleus and lacks PIP3 phosphatase activity.
Fig. 4: Pten-NOLC1 promotes cancer cell growth and invasion in vitro and in vivo.
Fig. 5: Pten-NOLC1 interacts with genomic DNA and activates the expression of progrowth genes.
Fig. 6: Pten-NOLC1 fusion generates spontaneous liver cancer.

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Acknowledgements

We thank the Cell Biology Imaging Center of Univeristy of Pittsburgh for the support of cell imaging analysis.

Author information

Author notes

  1. Tianzhou Ma

    Present address: Department of Epidemiology and Biostatistics, University of Maryland School of Public Health, College Park, MD, 20742, USA

  2. Jun Zhang

    Present address: Department of Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA

Authors and Affiliations

  1. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA

    Jian-Hua Luo, Silvia Liu, Junyan Tao, Bao-Guo Ren, Zhang-Hui Chen, Michael Nalesnik, Kathleen Cieply, George K. Michalopoulos, Rohit Bhargava, Satdarshan Paul Monga & Yan-Ping Yu

  2. Department of Biology, Columbia University, 1212 Amsterdam Avenue, New York, NY, 10027, USA

    Katherine Luo & George Tseng

  3. Department of Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA

    Tianzhou Ma

  4. Department of Neurology, Northwestern University School of Medicine, Chicago, IL, 60611, USA

    Shi-Yuan Cheng

  5. Department of Pharmacology, Toxicology & Therapeutics, University of Kansas, Kansas City, KS, 66160, USA

    Qi Chen

  6. Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA

    Joel B. Nelson

  7. Department of Medicine, University of Iowa, Iowa City, IA, 52242, USA

    Jun Zhang

  8. Department of Pathology, University of Iowa, Iowa City, IA, 52242, USA

    Deqin Ma

  9. Department of Urology, University of Wisconsin Madison, Madison, WI, 53792, USA

    David Jarrard

  10. Department of Thoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA

    Arjun Pennathur & James D. Luketich

  11. Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA

    Donald B. DeFranco

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Correspondence to Jian-Hua Luo or Yan-Ping Yu.

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Luo, JH., Liu, S., Tao, J. et al. Pten-NOLC1 fusion promotes cancers involving MET and EGFR signalings. Oncogene 40, 1064–1076 (2021). https://doi.org/10.1038/s41388-020-01582-8

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