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Overexpressed PRR11-SKA2-miR301a/454 bidirectional transcription unit essentially and coordinately promotes PI3K-AKT pathway activation and lung cancer progression

Oncogene volume 45, pages 68–86 (2026)Cite this article

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Abstract

Gene pairing is a highly conserved and special mode of eukaryotic gene organization, and critically implicated in development and diseases including cancer. We previously found that PRR11 and SKA2 constitute a classic head-to-head gene pair. Here, we further demonstrate that PRR11, SKA2, and its intronic miR301a and miR454 constitute a more exquisite bidirectional transcription unit that are overexpressed in various types of cancers. Functional studies using lung cancer as a model system reveal that co-overexpression of PRR11, SKA2, miR301a and miR454 together remarkably accelerates cell growth, cell cycle progression and cell motility in lung cancer cells, and promotes tumor growth in mouse models in vivo, whereas CRISPRi-mediated repression of the entire transcription unit inhibits these malignant phenotypes. Mechanistically, the four component genes do not display any additive or synergistic effect, but rather compensate for each other for robustly sustained activation of PI3K-AKT pathway, with PRR11 interacting with GRB2, and SKA2 with EGFR. Notably, miR301a and miR454 exert their oncogenic functions at least partially via repressing PTEN translation. Moreover, the transcription unit presents as a prominent prognostic meta-marker for lung cancer. Collectively, these findings demonstrate the essential and coordinated roles of PRR11-SKA2-miR301a/454 bidirectional transcription unit in lung cancer progression, highlighting its potential diagnostic and therapeutic values in cancers.

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Fig. 1: PRR11-SKA2-miR301a/454 gene cluster is a prototypical bidirectional transcription unit coordinately upregulated in pan-cancer.
Fig. 2: PRR11-SKA2-miR301a/454 transcription unit is essential for lung cancer cell growth.
Fig. 3: PRR11 and SKA2 essentially and coordinately promote lung cancer progression.
Fig. 4: PRR11 and SKA2 interact with GRB2 and EGFR to activate PI3K-AKT pathway.
Fig. 5: miR301a and miR454 coordinately promote lung cancer cell growth.
Fig. 6: miR301a and miR454 are essential for lung cancer cell growth.
Fig. 7: miR301a and miR454 activate PI3K-AKT pathway at least via translation repression of PTEN.
Fig. 8: PRR11, SKA2, miR301a and miR454 coordinately promote lung cancer cell growth via PI3K-AKT pathway.
Fig. 9: Prognostic value of PRR11-SKA2-miR301a/454 transcription unit in lung cancer.
Fig. 10: Working model illustrating the essential and coordinated implication of PRR11-SKA2-miR301a/454 transcription unit during lung cancer progression.

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Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Material. The RNA-seq data used in this publication have been deposited in NCBI’s Gene Expression Omnibus and are accessible through GEO Series accession number GSE269696.

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Acknowledgements

We sincerely thank all our team members for their help in this work. We gratefully thank Ms. Xia Zhang for her excellent technical assistance at the confocal microscope, and Dr Anchao Song for assistance with statistical analyses.

Funding

National Natural Science Foundation of China (81672301, 82372630, 82403031); Chongqing Municipal Science and Technology Commission (CSTB2023NSCQ-BHX0098); CQMU Program for Youth Innovation in Future Medicine (W0143).

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Author notes

  1. These authors contributed equally: Tao Liu, Xiaofeng Zuo, Shijie Sun, Kailong Du.

Authors and Affiliations

  1. Department of Thoracic Surgery, The First Affiliated Hospital of Chongqing Medical University; Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China

    Tao Liu, Xiaofeng Zuo, Shijie Sun, Kailong Du, Chuntao Tao, Xing Xia, Linli Yu, Chunxue Zhang, Yitao Wang, Junhong Ye & Youquan Bu

  2. Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, China

    Tao Liu, Xiaofeng Zuo, Shijie Sun, Kailong Du, Chuntao Tao, Xing Xia, Linli Yu, Chunxue Zhang, Yitao Wang, Junhong Ye & Youquan Bu

  3. The Affiliated Yongchuan Hospital of Chongqing Medical University, Chongqing, China

    Tao Liu

  4. Laboratory Animal Center, Chongqing Medical University, Chongqing, China

    Zhengmei Yang

  5. Western Institute of Digital-Intelligent Medicine, Chongqing, China

    Youquan Bu

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Contributions

TL: Investigation; methodology; visualization; writing - original draft. XZ: Investigation; methodology. SS: Investigation; methodology. KD: Investigation; software. CT: Investigation; software. XX: Investigation. LY: Investigation. CZ: Investigation. ZY: Investigation. YW: Investigation. JY: Investigation; supervision. YB: Conceptualization; funding acquisition; supervision; writing - review & editing.

Corresponding authors

Correspondence to Junhong Ye or Youquan Bu.

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The authors declare no competing interests.

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The animal study was approved by Institutional Animal Care and Use of Chongqing Medical University (IACUC-CQMU) (approval no.: IACUC-CQMU-2023-0471). Ethical approval was not required for the studies on humans because the human cancer datasets used in this study were obtained from public databases of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The cell lines used in this study were all commercially available. The studies were conducted in accordance with the local legislation and institutional requirements.

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Liu, T., Zuo, X., Sun, S. et al. Overexpressed PRR11-SKA2-miR301a/454 bidirectional transcription unit essentially and coordinately promotes PI3K-AKT pathway activation and lung cancer progression. Oncogene 45, 68–86 (2026). https://doi.org/10.1038/s41388-025-03607-6

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