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GABPA inhibits invasion/metastasis in papillary thyroid carcinoma by regulating DICER1 expression

Oncogene volume 38, pages 965–979 (2019)Cite this article

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Abstract

The ETS family transcription factor GABPA is suggested as an oncogenic element, which is further supported by the recent reporting of it as the sole ETS member to activate the mutant TERT promoter in thyroid carcinomas (TC). However, it remains unclear how GABPA contributes to TC pathogenesis. The present study is designed to address this issue. TERT expression was significantly diminished in TERT promoter-mutated TC cells upon GABPA inhibition. Surprisingly, GABPA depletion led to robustly increased cellular invasion independently of TERT promoter mutations and TERT expression. DICER1, a component of the microRNA machinery, was identified as a downstream effector of GABPA. GABPA facilitated Dicer1 transcription while its depletion reduced Dicer1 expression. The mutation of the GABPA binding site in the DICER1 promoter led to diminished basal levels of DICER1 promoter activity and abolishment of GABPA-stimulated promoter activity as well. The forced DICER1 expression abrogated the invasiveness of GABPA-depleted TC cells. Consistently, the analyses of 93 patients with papillary thyroid carcinoma (PTC) revealed a positive correlation between GABPA and DICER1 expression. GABPA expression was negatively associated with TERT expression and promoter mutations, in contrast to published observations in cancer cell lines. Lower GABPA expression was associated with distant metastasis and shorter overall/disease-free survival in PTC patients. Similar results were obtained for PTC cases in the TCGA dataset. In addition, a positive correlation between GABPA and DICER1 expression was seen in multiple types of malignancies. Taken together, despite its stimulatory effect on the mutant TERT promoter and telomerase activation, GABPA may itself act as a tumor suppressor rather than an oncogenic factor to inhibit invasion/metastasis in TCs and be a useful predictor for patient outcomes.

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Acknowledgements

We thank Dr. J.K., Dr. J.F. Costello (University of California, San Francisco) for the TERT promoter reporters, Ms. L. Åhnfalk for excellent assistance in tumor tissue collection, Dr. B. Guan for evaluation of tumor colonies in mouse lung, and E. Berg (Karolinska Institutet) for expert consultations in the statistical analyses. The study was supported by grants from the Swedish Cancer Society, the Cancer Society in Stockholm, Stockholm County Council and Karolinska Institutet, and Shandong Provincial Natural Science Foundation, China (2016ZDJS07A09).

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  1. These authors contributed equally: Xiaotian Yuan, Ninni Mu, Na Wang.

Authors and Affiliations

  1. Reproductive Center, Shandong University, Jinan, 250013, PR China

    Xiaotian Yuan

  2. Department of Medicine-Solna, Karolinska Institutet, Karolinska University Hospital CMM, SE-171 76, Stockholm, Sweden

    Xiaotian Yuan, Klas Strååt, Yanxia Guo & Dawei Xu

  3. Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital CCK, SE-171 76, Stockholm, Sweden

    Ninni Mu, Na Wang, Anastasios Sofiadis, Adam Stenman, C. Christofer Juhlin & Catharina Larsson

  4. Central Research Laboratory, Shandong University Second Hospital, Jinan, 250033, PR China

    Yanxia Guo, Kailin Li, Guanghui Cheng, Lu Zhang & Feng Kong

  5. Division of Oncology and Pathology, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund, Sweden

    Lars Ekblad

  6. Division of Oto-rhino-laryngology, Head and Neck Surgery, Department of Clinical Sciences Lund, Skåne University Hospital, Lund University, Lund, Sweden

    Johan Wennerberg

  7. Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, SE-171 76, Stockholm, Sweden

    Inga-Lena Nilsson

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Yuan, X., Mu, N., Wang, N. et al. GABPA inhibits invasion/metastasis in papillary thyroid carcinoma by regulating DICER1 expression. Oncogene 38, 965–979 (2019). https://doi.org/10.1038/s41388-018-0483-x

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