{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:35:45Z","timestamp":1787160945202,"version":"build-2736575974"},"reference-count":46,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,9,25]],"date-time":"2020-09-25T00:00:00Z","timestamp":1600992000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fundamental Research Funds of Zhejiang Sci-Tech University","award":["2020Y002"],"award-info":[{"award-number":["2020Y002"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81728012"],"award-info":[{"award-number":["81728012"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["LY18H160065"],"award-info":[{"award-number":["LY18H160065"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cancers"],"abstract":"<jats:p>Malignant mesothelioma is a locally aggressive and highly lethal neoplasm. Dysregulation and activation of Gas6\/AXL tyrosine kinase signaling are associated with mesothelioma progression, but the mechanisms of these AXL tumorigenic roles are poorly understood. p53 mutants in lung carcinoma upregulate AXL expression by binding and acetylating the AXL promoter. Although TP53 mutations are uncommon in mesothelioma, we hypothesized that these tumors might have alternative feedback mechanisms between AXL and p53. In the current report, we investigated AXL regulation of TP53 transcription, expression, and biological function in mesothelioma. AXL expression was stronger in mesothelioma than most of the other tumor types from the TCGA gene expression profile dataset. AXL knockdown by shRNA induced wild-type and mutant p53 expression in mesothelioma cell lines, suggesting that AXL pro-tumorigenic roles result in part from the suppression of p53 function. Likewise, induced AXL inhibited expression of wild type p53 in COS-7 cells and 293T cells. Immunofluorescence staining showed nuclear colocalization of AXL and p53; however, association of AXL and p53 was not demonstrated in immunoprecipitation complexes. The AXL effects on p53 expression resulted from the inhibition of TP53 transcription, as demonstrated by qRT-PCR after AXL silencing and TP53 promotor dual luciferase activity assays. Chromatin immunoprecipitation-qPCR and sequencing showed that AXL bound to the initial 600 bp sequence at the 5\u2032 end of the TP53 promoter. AXL inhibition (shRNA or R428) reduced mesothelioma cell viability, migration, and invasion, whereas TP53 shRNA knockdown attenuated antiproliferative, migration, and invasive effects of AXL silencing or AXL inactivation in these cells. These studies demonstrate a novel feedback regulation loop between AXL and p53, and provide a rationale for mesothelioma therapies targeting AXL\/p53 signaling.<\/jats:p>","DOI":"10.3390\/cancers12102757","type":"journal-article","created":{"date-parts":[[2020,9,25]],"date-time":"2020-09-25T09:15:23Z","timestamp":1601025323000},"page":"2757","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["AXL Inactivation Inhibits Mesothelioma Growth and Migration via Regulation of p53 Expression"],"prefix":"10.3390","volume":"12","author":[{"given":"Wei","family":"Song","sequence":"first","affiliation":[{"name":"Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Wang","sequence":"additional","affiliation":[{"name":"Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minmin","family":"Lu","sequence":"additional","affiliation":[{"name":"Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxin","family":"Ni","sequence":"additional","affiliation":[{"name":"Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nacef","family":"Bahri","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuihao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limin","family":"Chen","sequence":"additional","affiliation":[{"name":"Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuehong","family":"Wu","sequence":"additional","affiliation":[{"name":"Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieqiong","family":"Qiu","sequence":"additional","affiliation":[{"name":"Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan A.","family":"Fletcher","sequence":"additional","affiliation":[{"name":"Department of Pathology, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6311-9442","authenticated-orcid":false,"given":"Wen-Bin","family":"Ou","sequence":"additional","affiliation":[{"name":"Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China"},{"name":"Department of Pathology, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,25]]},"reference":[{"key":"ref_1","unstructured":"Travis, W.D., Brambilla, E., Burke, A.P., Marx, A., and Nicholson, A.G. (2015). WHO Classification of Tumors of the Lung, Pleura, Thymus and Heart, IARC Press."},{"key":"ref_2","first-page":"402","article-title":"Mesothelioma: Scientific clues for prevention, diagnosis, and therapy","volume":"69","author":"Carbone","year":"2019","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"341","DOI":"10.2217\/imt-2017-0177","article-title":"Malignant mesothelioma clinical trial combines immunotherapy drugs","volume":"10","author":"Chatwal","year":"2018","journal-title":"Immunotherapy"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/S1470-2045(17)30169-9","article-title":"Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): Preliminary results from a non-randomised, open-label, phase 1b trial","volume":"18","author":"Alley","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1016\/j.jtho.2018.08.007","article-title":"Pembrolizumab as Palliative Immunotherapy in Malignant Pleural Mesothelioma","volume":"13","author":"Metaxas","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5438","DOI":"10.1158\/1078-0432.CCR-19-1836","article-title":"Nivo-lution in Mesothelioma","volume":"25","author":"Mansfield","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1093\/annonc\/mdy086","article-title":"Malignant pleural mesothelioma immune microenvironment and checkpoint expression: Correlation with clinical-pathological features and intratumor heterogeneity over time","volume":"29","author":"Pasello","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1038\/modpathol.2017.170","article-title":"Nuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: A multi-institutional study","volume":"31","author":"Rosen","year":"2018","journal-title":"Mod. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1016\/j.jtho.2018.07.002","article-title":"Pathologic Grading of Malignant Pleural Mesothelioma: An Evidence-Based Proposal","volume":"13","author":"Pelosi","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Pezzuto, F., Serio, G., Fortarezza, F., Scattone, A., Caporusso, C., Punzi, A., Cavone, D., Pennella, A., Marzullo, A., and Vimercati, L. (2020). Prognostic Value of Ki67 Percentage, WT-1 Expression and p16\/CDKN2A Deletion in Diffuse Malignant Peritoneal Mesothelioma: A Single-Centre Cohort Study. Diagnostics, 10.","DOI":"10.3390\/diagnostics10060386"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1038\/onc.2010.555","article-title":"AXL regulates mesothelioma proliferation and invasiveness","volume":"30","author":"Ou","year":"2011","journal-title":"Oncogene"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1593\/neo.101156","article-title":"Targeted inhibition of multiple receptor tyrosine kinases in mesothelioma","volume":"13","author":"Ou","year":"2011","journal-title":"Neoplasia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1158\/1535-7163.MCT-16-0105","article-title":"Strategies to Overcome Bypass Mechanisms Mediating Clinical Resistance to EGFR Tyrosine Kinase Inhibition in Lung Cancer","volume":"16","author":"Husain","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"13898","DOI":"10.1038\/ncomms13898","article-title":"Reprogramming the immunological microenvironment through radiation and targeting Axl","volume":"7","author":"Aguilera","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1158\/0008-5472.CAN-16-2976","article-title":"Lapatinib Resistance in Breast Cancer Cells Is Accompanied by Phosphorylation-Mediated Reprogramming of Glycolysis","volume":"77","author":"Ruprecht","year":"2017","journal-title":"Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1158\/0008-5472.CAN-09-2997","article-title":"R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer","volume":"70","author":"Holland","year":"2010","journal-title":"Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s00428-013-1435-z","article-title":"p53 mutations may be involved in malignant transformation of giant cell tumor of bone through interaction with GPX1","volume":"463","author":"Okubo","year":"2013","journal-title":"Virchows Arch."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"a001107","DOI":"10.1101\/cshperspect.a001107","article-title":"Mutant p53 gain-of-function in cancer","volume":"2","author":"Oren","year":"2010","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Pitolli, C., Wang, Y., Mancini, M., Shi, Y., Melino, G., and Amelio, I. (2019). Do Mutations Turn p53 into an Oncogene?. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20246241"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.cell.2009.04.050","article-title":"Modes of p53 regulation","volume":"137","author":"Kruse","year":"2009","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1177\/1947601912462719","article-title":"Gain-of-Function Activity of Mutant p53 in Lung Cancer through Up-Regulation of Receptor Protein Tyrosine Kinase Axl","volume":"3","author":"Vaughan","year":"2012","journal-title":"Genes Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/leu.2013.298","article-title":"The tumor suppressor axis p53\/miR-34a regulates Axl expression in B-cell chronic lymphocytic leukemia: Implications for therapy in p53-defective CLL patients","volume":"28","author":"Boysen","year":"2014","journal-title":"Leukemia"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.3748\/wjg.v23.i19.3440","article-title":"Role of AXL in invasion and drug resistance of colon and breast cancer cells and its association with p53 alterations","volume":"23","author":"Nair","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1038\/bjc.2016.331","article-title":"Co-targeting of FAK and MDM2 triggers additive anti-proliferative effects in mesothelioma via a coordinated reactivation of p53","volume":"115","author":"Ou","year":"2016","journal-title":"Br. J. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1593\/neo.06148","article-title":"p53-induced apoptosis occurs in the absence of p14(ARF) in malignant pleural mesothelioma","volume":"8","author":"Belyanskaya","year":"2006","journal-title":"Neoplasia"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2577","DOI":"10.1080\/15384101.2018.1553335","article-title":"Activated tyrosine kinases in gastrointestinal stromal tumor with loss of KIT oncoprotein expression","volume":"17","author":"Tu","year":"2018","journal-title":"Cell Cycle"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1158\/2159-8290.CD-18-0804","article-title":"Integrative Molecular Characterization of Malignant Pleural Mesothelioma","volume":"8","author":"Hmeljak","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1038\/bjc.2014.220","article-title":"Multipoint targeting of the PI3K\/mTOR pathway in mesothelioma","volume":"110","author":"Zhou","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_29","first-page":"2610","article-title":"p53 and Kirsten-ras mutations in human mesothelioma cell lines","volume":"52","author":"Metcalf","year":"1992","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"32652","DOI":"10.18632\/oncotarget.8999","article-title":"Downregulation of cyclin D1 sensitizes cancer cells to MDM2 antagonist Nutlin-3","volume":"7","author":"Yang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"10510","DOI":"10.18632\/oncotarget.3230","article-title":"HDACi inhibits liposarcoma via targeting of the MDM2-p53 signaling axis and PTEN, irrespective of p53 mutational status","volume":"6","author":"Ou","year":"2015","journal-title":"Oncotarget"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3693","DOI":"10.1111\/febs.13342","article-title":"Proteolytic cleavage, trafficking, and functions of nuclear receptor tyrosine kinases","volume":"282","author":"Chen","year":"2015","journal-title":"FEBS J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.ccr.2005.05.007","article-title":"Nuclear interaction of EGFR and STAT3 in the activation of the iNOS\/NO pathway","volume":"7","author":"Lo","year":"2005","journal-title":"Cancer Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.ccr.2004.07.012","article-title":"Binding at and transactivation of the COX-2 promoter by nuclear tyrosine kinase receptor ErbB-2","volume":"6","author":"Wang","year":"2004","journal-title":"Cancer Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2401","DOI":"10.1091\/mbc.e08-06-0600","article-title":"Fibroblast growth factor receptor-1 (FGFR1) nuclear dynamics reveal a novel mechanism in transcription control","volume":"20","author":"Lee","year":"2009","journal-title":"Mol. Biol. Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6550","DOI":"10.1038\/s41388-019-0900-9","article-title":"Nuclear KIT induces a NFKBIB-RELA-KIT autoregulatory loop in imatinib-resistant gastrointestinal stromal tumors","volume":"38","author":"Hsueh","year":"2019","journal-title":"Oncogene"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1096\/fj.201600702R","article-title":"Regulated intramembrane proteolysis of the AXL receptor kinase generates an intracellular domain that localizes in the nucleus of cancer cells","volume":"31","author":"Lu","year":"2017","journal-title":"FASEB J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1093\/jmcb\/mjw045","article-title":"AXL receptor signalling suppresses p53 in melanoma through stabilization of the MDMX-MDM2 complex","volume":"9","author":"Luo","year":"2017","journal-title":"J. Mol. Cell. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6615","DOI":"10.1038\/s41388-019-0894-3","article-title":"Cyclin D1 is a mediator of gastrointestinal stromal tumor KIT-independence","volume":"38","author":"Ou","year":"2019","journal-title":"Oncogene"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1128\/MCB.16.3.859","article-title":"Regulation of p16CDKN2 expression and its implications for cell immortalization and senescence","volume":"16","author":"Hara","year":"1996","journal-title":"Mol. Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1038\/35016125","article-title":"Compromised HOXA5 function can limit p53 expression in human breast tumours","volume":"405","author":"Raman","year":"2000","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1182\/blood.V74.3.940.940","article-title":"Expression of colony-stimulating factor genes by normal human mesothelial cells and human malignant mesothelioma cells lines in vitro","volume":"74","author":"Demetri","year":"1989","journal-title":"Blood"},{"key":"ref_43","first-page":"8118","article-title":"KIT Activation Is a Ubiquitous Feature of Gastrointestinal Stromal Tumors","volume":"61","author":"Rubin","year":"2001","journal-title":"Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/1476-4598-10-125","article-title":"Targeting HSP90 in ovarian cancers with multiple receptor tyrosine kinase coactivation","volume":"10","author":"Jiao","year":"2011","journal-title":"Mol. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Malard, V., Berenguer, F., Prat, O., Ruat, S., Steinmetz, G., and Quemeneur, E. (2007). Global gene expression profiling in human lung cells exposed to cobalt. BMC Genomics, 8.","DOI":"10.1186\/1471-2164-8-147"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/S1525-1578(10)60704-0","article-title":"Determination of cyclin D1 and CD20 mRNA levels by real-time quantitative RT-PCR from archival tissue sections of mantle cell lymphoma and other non-Hodgkin\u2019s lymphomas","volume":"4","author":"Thomazy","year":"2002","journal-title":"J. Mol. Diagn."}],"updated-by":[{"DOI":"10.3390\/cancers18162663","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2020,9,25]],"date-time":"2020-09-25T00:00:00Z","timestamp":1600992000000}}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/10\/2757\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T16:46:26Z","timestamp":1787157986000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/10\/2757"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,25]]},"references-count":46,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,10]]}},"alternative-id":["cancers12102757"],"URL":"https:\/\/doi.org\/10.3390\/cancers12102757","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,25]]}}}