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Therapeutic targeting of TNIK in papillary thyroid carcinoma: a novel approach for tumor growth suppression

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Abstract

Papillary thyroid carcinoma (PTC) is a common endocrine malignancy. The pathology of PTC is far from clear. As a kinase that can be targeted, the role of TNIK in PTC has not been investigated. This study was focused on the effects and molecular mechanisms of TNIK in PTC. Both public datasets and clinical specimens were used to verify TNIK expression. The effects of TNIK were investigated in both cell lines and mice models. Transcriptome analysis was used to explore the underlying mechanism of TNIK. Immunofluorescence, wound healing, and qRT-PCR assays were used to validate the mechanism of TNIK in PTC. The therapeutic effects of TNIK inhibitor NCB-0846 were evaluated by flow cytometry, western blot, and subcutaneous xenografts mice. TNIK expression was upregulated in PTC tissues. TNIK knockdown could suppress cell proliferation and tumor growth in no matter cell models or nude mice. The transcriptome analysis, GO enrichment analysis, and GSEA analysis results indicated TNIK was highly correlated with cytoskeleton, cell motility, and Wnt pathways. The mechanistic studies demonstrated that TNIK regulated cytoskeleton remodeling and promoted cell migration. NCB-0846 significantly inhibited TNIK kinase activity, induced cell apoptosis, and activated apoptosis-related proteins in a dose-dependent manner. In addition, NCB-0846 inhibited tumor growth in tumor-bearing mice. In summary, we proposed a novel regulatory mechanism in which TNIK-mediated cytoskeleton remodeling and cell migration to regulate tumor progression in PTC. TNIK is a therapeutic target in PTC and NCB-0846 would act as a novel targeted drug for PTC therapy.

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

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Funding

This work was supported by the Beijing-Tianjin-Hebei Integration Project (No. J200004, 20JCZXJC00120), Beijing Research Ward Demonstration Unit (BCRW202101), Beijing municipal science & technology commission (No. Z201100005520077), and Beijing Hospitals Authority Innovation Studio of Young Staff Funding Support (No. 202126).

Author information

Author notes

  1. Ruqian Zhang and Yongbo Yu have contributed equally to this work.

Authors and Affiliations

  1. Beijing Key Laboratory for Pediatric Diseases of Otolaryngology, Head and Neck Surgery, MOE Key Laboratory of Major Diseases in Children, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health (NCCH), Beijing, China

    Ruqian Zhang, Yongbo Yu, Yeran Yang, Xuan Zhang, Yan Chang, Yongli Guo & Xin Ni

  2. Biobank for Clinical Data and Samples in Pediatrics, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health (NCCH), Beijing, 100045, China

    Yongbo Yu, Yongli Guo & Xin Ni

  3. Department of Pathology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health (NCCH), Beijing, China

    Meng Zhang

  4. Department of Otolaryngology, Head and Neck Surgery, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health (NCCH), Beijing, 100045, People’s Republic of China

    Shengcai Wang & Xin Ni

  5. Department of Thyroid and Neck Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China

    Linfei Hu & Xiangqian Zheng

  6. Department of Otolaryngology Head and Neck Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei, China

    Jiali Li & Ruili Zhao

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  1. Ruqian Zhang
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Contributions

XN and YLG designed the experiment and revised the paper; RQZ and YBY performed most of the experiments and wrote the draft; YRY and MZ contributed to bioinformatic analysis; SCW and JLL performed tumor tissue collection and immunohistochemistry detection; XZ, YC, and LFH cultured the cells; XQZ and RLZ conducted the statistical analysis. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Yongli Guo or Xin Ni.

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The authors declare no competing interest.

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The Ethics Committees of Beijing Children’s Hospital approved this study.

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Zhang, R., Yu, Y., Yang, Y. et al. Therapeutic targeting of TNIK in papillary thyroid carcinoma: a novel approach for tumor growth suppression. Med Oncol 41, 160 (2024). https://doi.org/10.1007/s12032-024-02380-y

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