ARHGAP36 regulates proliferation and migration in papillary thyroid carcinoma cells

in Journal of Molecular Endocrinology
View More View Less
  • 1 Department of Thyroid, Parathyroid, Breast and Hernia Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, People’s Republic of China

Correspondence should be addressed to Z Yang: yangzhililaoshi@126.com

*(T Yan and W Qiu contributed equally to this work)

Restricted access

The diagnosis and treatment of recurrence and metastasis in papillary thyroid carcinoma (PTC) are still clinical challenges. One of the key factors is the lack of specific diagnostic markers and therapeutic targets for recurrence and metastasis. Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful approach to find specific biomarkers by dissecting expression profiling in human cancers at the resolution of individual cells. Here, we investigated cell profiles of the primary tumor and lymph node metastasis and paracancerous normal tissues in one PTC patient using scRNA-seq, and compared individual cell gene expression differences. The transcriptomes of 11,805 single cells were profiled, and malignant cells exhibited a profound transcriptional overlap between primary and metastatic lesions, but there were differences in the composition and quantity of non-malignant cells. ARHGAP36 was one of the genes that were highly expressed in almost all of the primary and metastatic malignant cells without non-malignant or normal follicular cells and was then confirmed by immunostaining in a sample cohort. Compared with the paracancerous normal tissue, the expression of ARHGAP36 in primary and metastatic carcinoma tissues was significantly higher as assayed by qRT-PCR. ARHGAP36 knockdown significantly inhibited the proliferation and migration of PTC cells in vitro and involved several proliferation and migration-associated signaling pathways by RNA seq. Our study demonstrated that ARHGAP36 is exclusively expressed in the malignant cells of primary PTC, as well as metastatic lesions, and regulates their proliferation and migration, meaning it can be used as a potential diagnostic marker and therapeutic target molecule.

 

Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 177 177 177
Full Text Views 79 79 79
PDF Downloads 31 31 31
  • Azizi E, Carr AJ, Plitas G, Cornish AE, Konopacki C, Prabhakaran S, Nainys J, Wu K, Kiseliovas V & Setty M et al. 2018 Single-cell map of diverse immune phenotypes in the breast tumor microenvironment. Cell 174 1293 .e361308.e36. (https://doi.org/10.1016/j.cell.2018.05.060)

    • Search Google Scholar
    • Export Citation
  • Beckmann PJ, Larson JD, Larsson AT, Ostergaard JP, Wagner S & Rahrmann EP, Shamsan G, Otto GM, Williams RL & Wang J et al. 2019 Sleeping beauty insertional mutagenesis reveals important genetic drivers of central nervous system embryonal tumors. Cancer Research 79 905 917.

    • Search Google Scholar
    • Export Citation
  • Cabanillas ME, Ryder M & Jimenez C 2019 Targeted therapy for advanced thyroid cancer: kinase inhibitors and beyond. Endocrine Reviews 40 15731604. (https://doi.org/10.1210/er.2019-00007)

    • Search Google Scholar
    • Export Citation
  • Cancer Genome Atlas Research Network 2014 Integrated genomic characterization of papillary thyroid carcinoma. Cell 159 6766 90. (https://doi.org/10.1016/j.cell.2014.09.050)

    • Search Google Scholar
    • Export Citation
  • Chmielik E, Rusinek D, Oczko-Wojciechowska M, Jarzab M, Krajewska J, Czarniecka A & Jarzab B 2018 Heterogeneity of thyroid cancer. Pathobiology 85 117129. (https://doi.org/10.1159/000486422)

    • Search Google Scholar
    • Export Citation
  • Cibas ES & Ali SZ 2017 The 2017 Bethesda system for reporting thyroid cytopathology. Thyroid 27 13411346. (https://doi.org/10.1089/thy.2017.0500)

    • Search Google Scholar
    • Export Citation
  • Croise P, Houy S, Gand M, Lanoix J, Calco V, Toth P, Brunaud L, Lomazzi S, Paramithiotis E & Chelsky D et al. 2016 Cdc42 and Rac1 activity is reduced in human pheochromocytoma and correlates with FARP1 and ARHGEF1 expression. Endocrine-Related Cancer 23 2812 93. (https://doi.org/10.1530/ERC-15-0502)

    • Search Google Scholar
    • Export Citation
  • Ding Z, Ke R, Zhang Y, Fan Y & Fan J 2019 FOXE1 inhibits cell proliferation, migration and invasion of papillary thyroid cancer by regulating PDGFA. Molecular and Cellular Endocrinology 493 110420. (https://doi.org/10.1016/j.mce.2019.03.010)

    • Search Google Scholar
    • Export Citation
  • Dong W, Horiuchi K, Tokumitsu H, Sakamoto A, Noguchi E, Ueda Y & Okamoto T 2019 Time-varying pattern of mortality and recurrence from papillary thyroid cancer: lessons from a long-term follow-up. Thyroid 29 802808. (https://doi.org/10.1089/thy.2018.0128)

    • Search Google Scholar
    • Export Citation
  • Eccles RL, Czajkowski MT, Barth C, Muller PM, Mcshane E, Grunwald S, Beaudette P, Mecklenburg N, Volkmer R & Zuhlke K et al. 2016 Bimodal antagonism of PKA signalling by ARHGAP36. Nature Communications 7 12963. (https://doi.org/10.1038/ncomms12963)

    • Search Google Scholar
    • Export Citation
  • Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S, Danielsson A & Edlund K et al. 2014 Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Molecular and Cellular Proteomics 13 397406. (https://doi.org/10.1074/mcp.M113.035600)

    • Search Google Scholar
    • Export Citation
  • Fu H, Cheng L, Jin Y, Cheng L, Liu M & Chen L 2019 MAPK inhibitors enhance HDAC inhibitor-induced redifferentiation in papillary thyroid cancer cells harboring BRAFV600E: an in vitro study. Molecular Therapy Oncolytics 12 235245. (https://doi.org/10.1016/j.omto.2019.01.007)

    • Search Google Scholar
    • Export Citation
  • Gugnoni M, Manicardi V, Torricelli F, Sauta E, Bellazzi R, Manzotti G, Vitale E, De Biase D, Piana S & Ciarrocchi A 2020 Linc00941 is a novel transforming growth factor β target that primes papillary thyroid cancer metastatic behavior by regulating the expression of cadherin 6. Thyroid [epub]. (https://doi.org/10.1089/thy.2020.0001)

    • Search Google Scholar
    • Export Citation
  • Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM & Schlumberger M et al. 2016 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association Guidelines Task Force on thyroid nodules and differentiated thyroid cancer. Thyroid 26 1133. (https://doi.org/10.1089/thy.2015.0020)

    • Search Google Scholar
    • Export Citation
  • Meireles AM, Preto A, Rocha AS, Rebocho AP, Máximo V, Pereira-Castro I, Moreira S, Feijão T, Botelho T & Marques R et al. 2007 Molecular and genotypic characterization of human thyroid follicular cell carcinoma-derived cell lines. Thyroid 17 7077 15. (https://doi.org/10.1089/thy.2007.0097)

    • Search Google Scholar
    • Export Citation
  • Nam H, Jeon S, An H, Yoo J, Lee HJ, Lee SK & Lee S 2019 Critical roles of ARHGAP36 as a signal transduction mediator of Shh pathway in lateral motor columnar specification. eLife 8 e46683. (https://doi.org/10.7554/eLife.46683)

    • Search Google Scholar
    • Export Citation
  • Peng J, Sun BF, Chen CY, Zhou JY, Chen YS, Chen H, Liu L, Huang D, Jiang J & Cui GS et al. 2019 Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma. Cell Research 29 725738. (https://doi.org/10.1038/s41422-019-0195-y)

    • Search Google Scholar
    • Export Citation
  • Puram SV, Tirosh I, Parikh AS, Patel AP, Yizhak K, Gillespie S, Rodman C, Luo CL, Mroz EA & Emerick KS et al. 2017 Single-cell transcriptomic analysis of primary and metastatic tumor ecosystems in head and neck. Cancer Cell 171 16 1 1 .e2416 24.e24.

    • Search Google Scholar
    • Export Citation
  • Rack PG, Ni J, Payumo AY, Nguyen V, Crapster JA, Hovestadt V, Kool M, Jones DT, Mich JK & Firestone AJ et al. 2014 Arhgap36-dependent activation of Gli transcription factors. PNAS 111 110611106 6. (https://doi.org/10.1073/pnas.1322362111)

    • Search Google Scholar
    • Export Citation
  • Raleigh DR & Reiter JF 2019 Misactivation of Hedgehog signaling causes inherited and sporadic cancers. Journal of Clinical Investigation 129 465475. (https://doi.org/10.1172/JCI120850)

    • Search Google Scholar
    • Export Citation
  • Siegelr RL, Miller KD & Jemal A 2020 Cancer statistics, 2020. CA: A Cancer Journal for Clinicians 70 730. (https://doi.org/10.3322/caac.21590)

    • Search Google Scholar
    • Export Citation
  • Stark R, Grzelak M & Hadfield J 2019 RNA sequencing: the teenage years. Nature Reviews: Genetics 20 631656. (https://doi.org/10.1038/s41576-019-0150-2)

    • Search Google Scholar
    • Export Citation
  • Suva ML & Tirosh I 2019 Single-cell RNA sequencing in cancer: lessons learned and emerging challenges. Molecular Cell 75 712. (https://doi.org/10.1016/j.molcel.2019.05.003)

    • Search Google Scholar
    • Export Citation
  • Xing M 2013 Molecular pathogenesis and mechanisms of thyroid cancer. Nature Reviews: Cancer 13 1841 99. (https://doi.org/10.1038/nrc3431)

    • Search Google Scholar
    • Export Citation
  • Xu X, Lu Y, Li Y & Prinz RA 2017 Sonic hedgehog signaling in thyroid cancer. Frontiers in Endocrinology 8 284. (https://doi.org/10.3389/fendo.2017.00284)

    • Search Google Scholar
    • Export Citation
  • Yakushina VD, Lerner LV & Lavrov AV 2018 Gene fusions in thyroid cancer. Thyroid 28 158167. (https://doi.org/10.1089/thy.2017.0318)

  • Young MD, Mitchell TJ, Vieira Braga FA, Tran MGB, Stewart BJ, Ferdinand JR, Collord G, Botting RA, Popescu DM & Loudon KW et al. 2018 Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors. Science 361 594599. (https://doi.org/10.1126/science.aat1699)

    • Search Google Scholar
    • Export Citation
  • Zhang B, Zhuang T, Lin Q, Yang B, Xu X, Xin G, Zhu S, Wang G, Yu B & Zhang T et al. 2019 Patched1-ArhGAP36-PKA-inversin axis determines the ciliary translocation of smoothened for Sonic Hedgehog pathway activation. PNAS 116 874879. (https://doi.org/10.1073/pnas.1804042116)

    • Search Google Scholar
    • Export Citation