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CLIP170 inhibits the metastasis and EMT of papillary thyroid cancer through the TGF-β pathway

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Abstract

Metastasis poses a significant challenge in combating tumors. Even in papillary thyroid cancer (PTC), which typically exhibits a favorable prognosis, high recurrence rates are attributed to metastasis. Cytoplasmic linker protein 170 (CLIP170) functions as a classical microtubule plus-end tracking protein (+TIP) and has shown close association with cell migration. Nevertheless, the specific impact of CLIP170 on PTC cells remains to be elucidated. Our analysis of the GEO and TCGA databases unveiled an association between CLIP170 and the progression of PTC. To explore the impact of CLIP170 on PTC cells, we conducted various assays. We evaluated its effects through CCK-8, wound healing assay, and transwell assay after knocking down CLIP170. Additionally, the influence of CLIP170 on the cellular actin structure was examined via immunofluorescence; we further investigated the molecular expressions of epithelial-mesenchymal transition (EMT) and the transforming growth factor-β (TGF-β) signaling pathways through Western blotting and RT-qPCR. These findings were substantiated through an in vivo nude mouse model of lung metastasis. We observed a decreased expression of CLIP170 in PTC in contrast to normal thyroid tissue. Functionally, the knockdown of CLIP170 (CLIP170KD) notably enhanced the metastatic potential and EMT of PTC cells, both in vitro and in vivo. Mechanistically, CLIP170KD triggered the activation of the TGF-β pathway, subsequently promoting tumor cell migration, invasion, and EMT. Remarkably, the TGF-β inhibitor LY2157299 effectively countered TGF-β activity and significantly reversed tumor metastasis and EMT induced by CLIP170 knockdown. In summary, these findings collectively propose CLIP170 as a promising therapeutic target to mitigate metastatic tendencies in PTC.

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Acknowledgements

This work was supported by the Gansu Province Key R&D Program [21YF5FA126], Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital [CY2021-QN-B16], the Gansu Province Natural Science Foundation [22JR11RA055] and [23JRRA1634], the Lanzhou Science and technology project (grant no.2021-1-104), and Gansu Provincial People's Hospital Intramural Research Fund [ZX-62000001-2023-377].

Funding

This work was supported by the Gansu Province Key R&D Program [21YF5FA126], Cuiying Scientific and Technological Innovation Program of Lanzhou University Second Hospital [CY2021-QN-B16], the Gansu Province Natural Science Foundation [22JR11RA055] and [23JRRA1634], and Gansu Provincial People's Hospital Intramural Research Fund [ZX-62000001-2023-377].

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  1. Binyuan Ma and Yaxin Xu contributed equally to this work.

Authors and Affiliations

  1. Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730000, China

    Binyuan Ma, Hongwei Gao, Yunyan Pan & Chongge You

  2. Laboratory Medicine Center, Gansu Provincial Hospital, Lanzhou, 730000, China

    Yaxin Xu

  3. Department of Laboratory, Gansu Third People’s Hospital, Lanzhou, 730000, China

    Yinggui Yang

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  1. Binyuan Ma
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Contributions

BM and YX carried out the experiments and writing-original draft; HG and YY contributed toward study design and data analysis; and CY and YP contributed toward data analysis, interpretation, and revision of manuscript. All authors have reviewed the final version of the manuscript and approved it for publication.

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Correspondence to Yunyan Pan or Chongge You.

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Ethical approval was obtained from the Ethical Committee of Lanzhou University the Second Hospital (22021A-544).

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12032_2024_2355_MOESM1_ESM.tif

Supplementary Fig. 1 CLIP170KD regulated TGF-β pathway activation in PTC cells (A and B) The mRNA expression of key signaling molecules in the TGF-β signaling pathway.

12032_2024_2355_MOESM2_ESM.tif

Supplementary Fig. 2 TGF-β inhibitor rescued the metastasis and EMT induced by CLIP170 knockdown in PTC cells (A) Western blotting assay of Samd2/3 phosphorylation inTPC-1 cells in a dose-dependent manner (5–20 uM) adding the LY2157299. (B) Wound healing after adding TGF-β inhibitor.*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

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Ma, B., Xu, Y., Gao, H. et al. CLIP170 inhibits the metastasis and EMT of papillary thyroid cancer through the TGF-β pathway. Med Oncol 41, 137 (2024). https://doi.org/10.1007/s12032-024-02355-z

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