{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T15:50:19Z","timestamp":1792165819036,"version":"4.4.0"},"reference-count":42,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,26]],"date-time":"2022-01-26T00:00:00Z","timestamp":1643155200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MINISTRY OF HIGHER EDUCATION MALAYSIA","award":["FRGS\/1\/2019\/SKK13\/USM\/01\/1"],"award-info":[{"award-number":["FRGS\/1\/2019\/SKK13\/USM\/01\/1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Abnormal expressions of CD74 and human leukocyte antigen-DR alpha (HLA-DRA) have been reported in various cancers, though their roles in cervical cancer remain unclear. This study aimed to evaluate the gene and protein expressions of CD74 and HLA-DRA in the progression from normal cervix to precancerous cervical intraepithelial neoplasia (CIN) and finally to squamous cell carcinoma (SCC). Materials and Methods: The gene expression profiles of CD74 and HLA-DRA were determined in formalin-fixed paraffin-embedded tissues, with three samples each from normal cervixes, human papillomavirus type 16\/18-positive, low-grade CIN (LGCIN), high-grade CIN (HGCIN), and squamous cell carcinoma (SCC) using Human Transcriptome Array 2.0. Immunohistochemical expression of the proteins was semi-quantitatively assessed in another cohort of tissue microarray samples comprising 7 normal cervix cases, 10 LGCIN, 10 HGCIN, and 95 SCC. Results: The transcriptomics profile and proteins\u2019 expression demonstrated similar trends of upregulation of CD74 and HLA-DRA from normal cervix to CIN and highest in SCC. There was a significant difference in both proteins\u2019 expression between the histological groups (p = 0.0001). CD74 and HLA-DRA expressions were significantly associated with CIN grade (p = 0.001 and p = 0.030, respectively) but not with the subjects\u2019 age or SCC stage. Further analysis revealed a positive correlation between CD74 and HLA-DRA proteins. Conclusions: CD74 appears to promote cervical carcinogenesis via oncogenic signalling mechanisms and may serve as a potential antitumour target. Additionally, the upregulation of HLA-DRA, often associated with stronger immunogenicity, could be a promising biomarker for developing immunotherapies.<\/jats:p>","DOI":"10.3390\/medicina58020190","type":"journal-article","created":{"date-parts":[[2022,1,26]],"date-time":"2022-01-26T11:02:53Z","timestamp":1643194973000},"page":"190","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["CD74 and HLA-DRA in Cervical Carcinogenesis: Potential Targets for Antitumour Therapy"],"prefix":"10.3390","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3773-1758","authenticated-orcid":false,"given":"Carol K.","family":"Balakrishnan","sequence":"first","affiliation":[{"name":"Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Pulau Pinang, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6707-9505","authenticated-orcid":false,"given":"Gee Jun","family":"Tye","sequence":"additional","affiliation":[{"name":"Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Pulau Pinang, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shandra Devi","family":"Balasubramaniam","sequence":"additional","affiliation":[{"name":"Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Pulau Pinang, Malaysia"},{"name":"Unit of Microbiology, Faculty of Medicine, AIMST University, Bedong 08100, Semeling, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6232-5703","authenticated-orcid":false,"given":"Gurjeet","family":"Kaur","sequence":"additional","affiliation":[{"name":"Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800, Pulau Pinang, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1159\/000449023","article-title":"Neoadjuvant and Adjuvant Chemotherapy of Cervical Cancer","volume":"39","author":"Mallmann","year":"2016","journal-title":"Oncol. Res. Treat."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S0140-6736(18)32470-X","article-title":"Cervical cancer","volume":"393","author":"Cohen","year":"2019","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1128\/CMR.16.1.1-17.2003","article-title":"Human papillomavirus and cervical cancer","volume":"16","author":"Burd","year":"2003","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Balasubramaniam, S.D., Balakrishnan, V., Oon, C.E., and Kaur, G. (2019). Key molecular events in cervical cancer development. Medicina, 55.","DOI":"10.3390\/medicina55070384"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1038\/nri3084","article-title":"Towards a systems understanding of MHC class i and MHC class II antigen presentation","volume":"11","author":"Neefjes","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Park, I.A., Hwang, S.-H., Song, I.H., Heo, S.-H., Kim, Y.-A., Bang, W.S., Park, H.S., Lee, M., Gong, G., and Lee, H.J. (2017). Expression of the MHC class II in triple-negative breast cancer is associated with tumor-infiltrating lymphocytes and interferon signaling. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0182786"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"250435","DOI":"10.1155\/2013\/250435","article-title":"Expression of the Classical and Nonclassical HLA Molecules in Breast Cancer","volume":"2013","author":"Silva","year":"2013","journal-title":"Int. J. Breast Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1002\/ijc.25106","article-title":"Lack of HLA class II antigen expression in microsatellite unstable colorectal carcinomas is caused by mutations in HLA class II regulatory genes","volume":"127","author":"Michel","year":"2010","journal-title":"Int. J. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1016\/S0344-0338(00)80080-1","article-title":"Loss of MHC class II expression is associated with a decrease of tumor-infiltrating T cells and an increase of metastatic potential of colorectal cancer: Immunohistological and histopathological analyses as compared with normal colonic mucosa and adenomas","volume":"196","author":"Warabi","year":"2000","journal-title":"Pathol. Res. Pract."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2980","DOI":"10.1002\/ijc.22266","article-title":"HLA-class II haplotype associations with ovarian cancer","volume":"119","author":"Arndt","year":"2006","journal-title":"Int. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5250","DOI":"10.1158\/1078-0432.CCR-18-0309","article-title":"Quantitative spatial profiling of PD-1\/PD-L1 interaction and HLA-DR\/IDO-1 predicts improved outcomes of anti-PD-1 therapies in metastatic melanoma","volume":"24","author":"Johnson","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2392","DOI":"10.1158\/1078-0432.CCR-18-3200","article-title":"Biological consequences of MHC-II expression by tumor cells in cancer","volume":"25","author":"Axelrod","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4886","DOI":"10.1096\/fj.12-211466","article-title":"Interaction of HLA-DR and CD74 at the cell surface of antigen-presenting cells by single particle image analysis","volume":"26","author":"Karakikes","year":"2012","journal-title":"FASEB J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"174","DOI":"10.5411\/wji.v4.i3.174","article-title":"Recent advances of cluster of differentiation 74 in cancer","volume":"4","author":"Liu","year":"2014","journal-title":"World J. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2273","DOI":"10.1007\/s13277-012-0489-x","article-title":"CD74: A potential novel target for triple-negative breast cancer","volume":"33","author":"Tian","year":"2012","journal-title":"Tumour Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1111\/j.1442-2042.2012.03128.x","article-title":"CD74 expression is increased in high-grade, invasive urothelial carcinoma of the bladder","volume":"20","author":"Choi","year":"2013","journal-title":"Int. J. Urol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1097\/00130404-200205000-00011","article-title":"The prognostic value of invariant chain (Ii) and Her-2\/neu expression in curatively resected colorectal cancer","volume":"8","author":"Rossi","year":"2002","journal-title":"Cancer J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.3892\/or.2013.2630","article-title":"CD74-ROS1 fusion transcripts in resected non-small cell lung carcinoma","volume":"30","author":"Matsuura","year":"2013","journal-title":"Oncol. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Sabbatino, F., Liguori, L., Polcaro, G., Salvato, I., Caramori, G., Salzano, F.A., Casolaro, V., Stellato, C., Col, J.D., and Pepe, S. (2020). Role of human leukocyte antigen system as a predictive biomarker for checkpoint-based immunotherapy in cancer patients. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197295"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e1171447","DOI":"10.1080\/2162402X.2016.1171447","article-title":"HLA class II antigen-processing pathway in tumors: Molecular defects and clinical relevance","volume":"6","author":"Seliger","year":"2017","journal-title":"Oncoimmunology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/j.1349-7006.2006.00137.x","article-title":"Strong HLA-DR antigen expression on cancer cells relates to better prognosis of colorectal cancer patients: Possible involvement of c-myc suppression by interferon-\u03b3 in situ","volume":"97","author":"Matsushita","year":"2006","journal-title":"Cancer Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1002\/ijc.20860","article-title":"Tumor HLA-DR expression linked to early intrahepatic recurrence of hepatocellular carcinoma","volume":"115","author":"Matoba","year":"2005","journal-title":"Int. J. Cancer"},{"key":"ref_24","first-page":"1","article-title":"Clinical Relevance of Co-Expression of HLA-DR \u03b1, CD74\/II and NFkB in Epithelial Ovarian Cancer: Identification of Prognostic and Therapeutical Biomarker Profile","volume":"2","author":"Madeira","year":"2020","journal-title":"SL Clin. Med. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.imbio.2006.05.005","article-title":"MHC class II molecules in tumour immunology: Prognostic marker and target for immune modulation","volume":"211","author":"Chamuleau","year":"2006","journal-title":"Immunobiology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1097\/IGC.0b013e31821c45b7","article-title":"Expression of macrophage migration inhibitory factor and CD74 in cervical squamous cell carcinoma","volume":"21","author":"Cheng","year":"2011","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1016\/j.ejca.2009.02.005","article-title":"Differential CD74 (major histocompatibility complex Class II invariant chain) expression in mouse and human intestinal adenomas","volume":"45","author":"Cuthbert","year":"2009","journal-title":"Eur. J. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1097\/00129039-200009000-00007","article-title":"Expression of MHC class II-associated invariant chain (Ii;CD74) in thymic epithelial neoplasms","volume":"8","author":"Datta","year":"2000","journal-title":"Appl. Immunohistochem. Mol. Morphol."},{"key":"ref_29","first-page":"1","article-title":"Enhanced expression of CD74 in gastrointestinal cancers and benign tissues","volume":"4","author":"Gold","year":"2011","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.immuni.2006.08.020","article-title":"CD44 Is the Signaling Component of the Macrophage Migration Inhibitory Factor-CD74 Receptor Complex","volume":"25","author":"Shi","year":"2006","journal-title":"Immunity"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1073\/pnas.1612195114","article-title":"CD74 is a novel transcription regulator","volume":"114","author":"Radomir","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"118026","DOI":"10.1016\/j.lfs.2020.118026","article-title":"Comparative transcriptomic profiling in HPV-associated cervical carcinogenesis: Implication of MHC class II and immunoglobulin heavy chain genes","volume":"256","author":"Balasubramaniam","year":"2020","journal-title":"Life Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.4161\/cbt.3.10.1142","article-title":"Anomalous expression of the HLA-DR \u03b1 and \u03b2 chains in ovarian and other cancers","volume":"3","author":"Rangel","year":"2004","journal-title":"Cancer Biol. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s41016-017-0090-7","article-title":"Expression of HLA-DR genes in gliomas: Correlation with clinicopathological features and prognosis","volume":"3","author":"Fan","year":"2017","journal-title":"Chin. Neurosurg. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1126\/science.1203486","article-title":"Cancer immunoediting: Integrating immunity\u2019s roles in cancer suppression and promotion","volume":"331","author":"Schreiber","year":"2011","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1200\/JCO.2017.77.3994","article-title":"Major histocompatibility complex class II and programmed death ligand 1 expression predict outcome after programmed death 1 blockade in classic Hodgkin lymphoma","volume":"36","author":"Roemer","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4251","DOI":"10.1182\/blood-2003-07-2365","article-title":"Loss of MHC class II gene and protein expression in diffuse large B-cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: A follow-up study from the Leukemia and Lymphoma Molecular","volume":"103","author":"Rimsza","year":"2004","journal-title":"Blood"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1002\/(SICI)1096-9896(199901)187:2<191::AID-PATH206>3.0.CO;2-3","article-title":"Lack of class II transactivator causes severe deficiency of HLA-DR expression in small cell lung cancer","volume":"187","author":"Yazawa","year":"1999","journal-title":"J. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1111\/imm.12136","article-title":"Histone deacetylase inhibitors activate CIITA and MHC class II antigen expression in diffuse large B-cell lymphoma","volume":"140","author":"Cycon","year":"2013","journal-title":"Immunology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/S0304-3835(01)00503-1","article-title":"chain expression in gastric cancer","volume":"168","author":"Ishigami","year":"2001","journal-title":"Cancer Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"71","DOI":"10.4236\/abcr.2015.43008","article-title":"Prognostic Value of CD74 and HLA-DR Expressions in Invasive Ductal Breast Cancer","volume":"4","author":"Yaprak","year":"2015","journal-title":"Adv. Breast Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/S0167-7799(00)01421-9","article-title":"Genetic modulation of tumor antigen presentation","volume":"18","author":"Xu","year":"2000","journal-title":"Trends Biotechnol."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/58\/2\/190\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:08:25Z","timestamp":1760134105000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/58\/2\/190"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,26]]},"references-count":42,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["medicina58020190"],"URL":"https:\/\/doi.org\/10.3390\/medicina58020190","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,26]]}}}