{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:39:22Z","timestamp":1760146762786,"version":"build-2065373602"},"reference-count":44,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T00:00:00Z","timestamp":1733702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Collaborative Health Initiative Research Program (CHIRP)","award":["IAA-A-HL-14-007"],"award-info":[{"award-number":["IAA-A-HL-14-007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Thyroid cancer is the most common endocrine malignancy in the United States, with an overall favorable prognosis. However, some patients experience poor outcomes due to the development of resistance to conventional therapies. Genetic alterations, including mutations in BRAF, Met, and p53, play critical roles in thyroid cancer progression, with the BRAF V600E mutation detected in over 60% of cases. This study investigates the tumor-suppressive role of Annexin A7 (ANXA7) in thyroid cancer, focusing on its potential impact on tumor behavior and therapeutic response. Our analysis, which included RNA sequencing and protein profiling, revealed reduced ANXA7 expression in thyroid cancer cells, particularly in those harboring the BRAF V600E mutation. Upon treatment with inhibitors targeting BRAF and MEK, ANXA7 expression increased, leading to reduced phosphorylation of ERK and activation of apoptotic pathways. Additionally, we identified the cyclin-dependent kinase inhibitor p21 as a key player in modulating resistance to BRAF inhibitors. Combination therapies aimed at concurrently increasing p21 and ANXA7 levels resulted in a marked enhancement of apoptosis. These findings suggest a previously uncharacterized regulatory network involving the ANXA7\/p21\/BRAF\/MAPK\/p53 axis, which may contribute to drug resistance in thyroid cancer. This study provides new insights into overcoming resistance to BRAF and MAPK inhibitors, with implications for treating thyroid cancer and potentially other BRAF-mutant tumors. Future efforts will focus on high-throughput screening approaches to explore ANXA7-targeted therapeutic strategies for thyroid cancer.<\/jats:p>","DOI":"10.3390\/ijms252313217","type":"journal-article","created":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T10:11:47Z","timestamp":1733739107000},"page":"13217","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Role of Annexin 7 (ANXA7) as a Tumor Suppressor and a Regulator of Drug Resistance in Thyroid Cancer"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2690-8178","authenticated-orcid":false,"given":"Alakesh","family":"Bera","sequence":"first","affiliation":[{"name":"Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"},{"name":"Department of Anesthesiology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Surya","family":"Radhakrishnan","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Narayanan","family":"Puthillathu","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madhan","family":"Subramanian","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nahbuma","family":"Gana","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Russ","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harvey B.","family":"Pollard","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8447-1330","authenticated-orcid":false,"given":"Meera","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"},{"name":"Department of Anesthesiology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,9]]},"reference":[{"key":"ref_1","unstructured":"Howlader, N., Noone, A.M., Krapcho, M., Miller, D., Bishop, K., Kosary, C.L., Yu, M., Ruhl, J., Tatalovich, Z., and Mariotto, A. (2017, April 15). SEER Cancer Statistics Review, 1975\u20132014, Available online: https:\/\/seer.cancer.gov\/csr\/1975_2014\/."},{"key":"ref_2","first-page":"30","article-title":"Diagnosis and treatment of patients with thyroid cancer","volume":"8","author":"Nguyen","year":"2015","journal-title":"Am. Health Drug Benefits"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1634\/theoncologist.2014-0182","article-title":"Novel approaches in anaplastic thyroid cancer therapy","volume":"19","author":"Hsu","year":"2014","journal-title":"Oncologist"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1200\/JCO.2014.59.3657","article-title":"BRAF mutation and thyroid cancer recurrence","volume":"33","author":"Yarchoan","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s00428-013-1521-2","article-title":"Prognostic biomarkers in thyroid cancer","volume":"464","author":"Soares","year":"2014","journal-title":"Virchows Arch."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1016\/j.surg.2013.06.024","article-title":"Clinical and therapeutic implications of Sprouty2 feedback dysregulation in BRAF V600E-mutation-positive papillary thyroid cancer","volume":"154","author":"Dultz","year":"2013","journal-title":"Surgery"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1038\/nature00766","article-title":"Mutations of the BRAF gene in human cancer","volume":"417","author":"Davies","year":"2002","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1001\/jama.2013.3190","article-title":"Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer","volume":"309","author":"Xing","year":"2013","journal-title":"JAMA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/nature24037","article-title":"Cancer drug addiction is relayed by an ERK2-dependent phenotype switch","volume":"550","author":"Kong","year":"2017","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1097\/PPO.0b013e318212dd3d","article-title":"Mechanism of cell adaptation: When and how do cancer cells develop chemoresistance?","volume":"17","author":"Fodale","year":"2011","journal-title":"Cancer J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"192","DOI":"10.18632\/aging.100296","article-title":"Roles of the Raf\/MEK\/ERK and PI3K\/PTEN\/Akt\/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging","volume":"3","author":"Steelman","year":"2011","journal-title":"Aging"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e9509","DOI":"10.1097\/MD.0000000000009509","article-title":"Aberrations and clinical significance of BRAF in malignant melanoma: A series of 60 cases in Chinese Uyghur","volume":"97","author":"Kang","year":"2018","journal-title":"Medicine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1001\/jama.2013.8598","article-title":"BRAF V600E mutation and papillary thyroid cancer\u2014In reply","volume":"310","author":"Xing","year":"2013","journal-title":"JAMA"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Srivastava, M., Leighton, X., Starr, J., Eidelman, O., and Pollard, H.B. (2014). Diverse effects of ANXA7 and p53 on LNCaP prostate cancer cells are associated with regulation of SGK1 transcription and phosphorylation of the SGK1 target FOXO3A. Biomed. Res. Int., 2014.","DOI":"10.1155\/2014\/193635"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/978-1-4939-6539-7_3","article-title":"ANXA7-GTPase as Tumor Suppressor: Mechanisms and Therapeutic Opportunities","volume":"1513","author":"Leighton","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Srivastava, M., Bera, A., Eidelman, O., Tran, M.B., Jozwik, C., Glasman, M., Leighton, X., Caohuy, H., and Pollard, H.B. (2023). A Dominant-Negative Mutant of ANXA7 Impairs Calcium Signaling and Enhances the Proliferation of Prostate Cancer Cells by Downregulating the IP3 Receptor and the PI3K\/mTOR Pathway. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24108818"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue-based map of the human proteome","volume":"347","author":"Uhlen","year":"2015","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/j.ccell.2017.01.005","article-title":"Characterization of Human Cancer Cell Lines by Reverse-phase Protein Arrays","volume":"31","author":"Li","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_19","first-page":"1775","article-title":"Complete coding sequence of a human B-raf cDNA and detection of B-raf protein kinase with isozyme specific antibodies","volume":"5","author":"Sithanandam","year":"1990","journal-title":"Oncogene"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1002\/ijc.23008","article-title":"ANXA7 expression represents hormone-relevant tumor suppression in different cancers","volume":"121","author":"Srivastava","year":"2007","journal-title":"Int. J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2528","DOI":"10.1002\/ijc.24592","article-title":"Annexin-A7 protects normal prostate cells and induces distinct patterns of RB-associated cytotoxicity in androgen-sensitive and -resistant prostate cancer cells","volume":"125","author":"Torosyan","year":"2009","journal-title":"Int. J. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10797","DOI":"10.1073\/pnas.93.20.10797","article-title":"Membrane fusion protein synexin (annexin VII) as a Ca2+\/GTP sensor in exocytotic secretion","volume":"93","author":"Caohuy","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1038\/nrm1661","article-title":"Annexins: Linking Ca2+ signalling to membrane dynamics","volume":"6","author":"Gerke","year":"2005","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S1054-3589(08)60701-2","article-title":"Synexin (annexin VII) hypothesis for Ca2+\/GTP-regulated exocytosis","volume":"42","author":"Pollard","year":"1998","journal-title":"Adv. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.4161\/cbt.21047","article-title":"Differential regulation of p21waf1 protein half-life by DNA damage and Nutlin-3 in p53 wild-type tumors and its therapeutic implications","volume":"13","author":"Chang","year":"2012","journal-title":"Cancer Biol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"23105","DOI":"10.1074\/jbc.M110.124990","article-title":"Persistent p21 expression after Nutlin-3a removal is associated with senescence-like arrest in 4N cells","volume":"285","author":"Shen","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1002\/jcb.22852","article-title":"p53 and p21(Waf1) are recruited to distinct PML-containing nuclear foci in irradiated and Nutlin-3a-treated U2OS cells","volume":"111","author":"Shen","year":"2010","journal-title":"J. Cell. Biochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1038\/nature09627","article-title":"COT drives resistance to RAF inhibition through MAP kinase pathway reactivation","volume":"468","author":"Johannessen","year":"2010","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1002\/hon.1023","article-title":"Real-time PCR-based analysis of BRAF V600E mutation in low and intermediate grade lymphomas confirms frequent occurrence in hairy cell leukaemia","volume":"30","author":"Ewalt","year":"2012","journal-title":"Hematol. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1097\/GIM.0b013e31818fa2db","article-title":"EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome","volume":"11","author":"Palomaki","year":"2009","journal-title":"Genet. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.3892\/ol.2015.3401","article-title":"Associations of the BRAF (V600E) mutation and p53 protein expression with clinicopathological features of papillary thyroid carcinomas patients","volume":"10","author":"Shin","year":"2015","journal-title":"Oncol. Lett."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Erdmann, S., Seidel, D., Jahnke, H.G., Eichler, M., Simon, J.C., and Robitzki, A.A. (2019). Induced cross-resistance of BRAF(V600E) melanoma cells to standard chemotherapeutic dacarbazine after chronic PLX4032 treatment. Sci. Rep., 9.","DOI":"10.1038\/s41598-018-37188-0"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.1038\/s41467-019-09438-w","article-title":"MEK1\/2 inhibitor withdrawal reverses acquired resistance driven by BRAF(V600E) amplification whereas KRAS(G13D) amplification promotes EMT-chemoresistance","volume":"10","author":"Sale","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.ccell.2014.11.018","article-title":"Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF\/MEK cotargeting but result in melanoma drug addiction","volume":"27","author":"Moriceau","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1083\/jcb.200608109","article-title":"Critical requirement for cell cycle inhibitors in sustaining nonproliferative states","volume":"176","author":"Pajalunga","year":"2007","journal-title":"J. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e365","DOI":"10.1038\/emm.2017.112","article-title":"Nutlin-3 enhances the bortezomib sensitivity of p53-defective cancer cells by inducing paraptosis","volume":"49","author":"Lee","year":"2017","journal-title":"Exp. Mol. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1089\/thy.2010.1646","article-title":"Genetic alterations in the phosphatidylinositol-3 kinase\/Akt pathway in thyroid cancer","volume":"20","author":"Xing","year":"2010","journal-title":"Thyroid"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3052","DOI":"10.1073\/pnas.85.9.3052","article-title":"Sequence analysis of the MYC oncogene involved in the t(8;14)(q24;q11) chromosome translocation in a human leukemia T-cell line indicates that putative regulatory regions are not altered","volume":"85","author":"Finver","year":"1988","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2658","DOI":"10.1101\/gad.13.20.2658","article-title":"Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis","volume":"13","author":"Eischen","year":"1999","journal-title":"Genes Dev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"v","DOI":"10.1038\/nmeth.f.353","article-title":"The Simple Western\u2122: A gel-free, blot-free, hands-free Western blotting reinvention","volume":"8","author":"Nguyen","year":"2011","journal-title":"Nat. Methods"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.ab.2013.07.022","article-title":"Absolute quantitation of endogenous proteins with precision and accuracy using a capillary Western system","volume":"442","author":"Chen","year":"2013","journal-title":"Anal. Biochem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"pl1","DOI":"10.1126\/scisignal.2004088","article-title":"Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal","volume":"6","author":"Gao","year":"2013","journal-title":"Sci. Signal."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data","volume":"2","author":"Cerami","year":"2012","journal-title":"Cancer Discov."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/nature11003","article-title":"The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity","volume":"483","author":"Barretina","year":"2012","journal-title":"Nature"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/23\/13217\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:50:43Z","timestamp":1760115043000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/23\/13217"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,9]]},"references-count":44,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ijms252313217"],"URL":"https:\/\/doi.org\/10.3390\/ijms252313217","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,12,9]]}}}