收稿日期: 2024-12-12
网络出版日期: 2025-09-05
基金资助
国家自然科学基金面上项目(82172883);广东省基础与应用基础研究基金项目(2022A1515012444)
Expression characteristics and diagnostic value of DHCR24 protein in cervical squamous intraepithelial lesions
Received date: 2024-12-12
Online published: 2025-09-05
目的 探究Δ（24）-胆甾醇还原酶（DHCR24）在子宫颈鳞状上皮内病变（SILs）组织中的表达及其在SILs病理诊断中的价值。 方法 采用免疫组织化学方法定量检测DHCR24、p16及Ki-67在51例正常宫颈组织，44例LSIL 和57例HSIL 中的表达，绘制受试者工作特征曲线（ROC）分析DHCR24、p16及Ki-67蛋白评估SILs分级的诊断效能。 结果 DHCR24、p16、Ki-67蛋白表达水平与SILs进展均呈正相关；ROC 结果显示，DHCR24在正常宫颈组织与LSIL之间的免疫组化评分截断值为0.114 5，LSIL与HSIL间截断值为0.196 9，在诊断LSIL时敏感度为79.55%，高于p16及Ki-67的15.91%与18.08%（P < 0.05）；DHCR24与p16联合鉴别正常宫颈组织与LSIL组织的ROC曲线下面积（AUC）为0.932（95%CI：0.878 ~ 0.986），高于p16与Ki-67联合的0.861（95%CI：0.785 ~ 0.936）；DHCR24与p16联合鉴别LSIL与HSIL的AUC为0.971（95%CI：0.946 ~ 0.997），高于p16与Ki-67联合的0.870（95%CI：0.790 ~ 0.949）。 结论 DHCR24与p16蛋白表达水平均可为SILs的分级提供参考依据，且二者联合可提高诊断效率；DHCR24免疫组化染色强度绘制的ROC曲线所衍生的截断值可以提高LSIL诊断的敏感度。
关键词： 子宫颈鳞状上皮内病变; Δ（24）-胆甾醇还原酶; p16
张弛 , 杜靖然 , 廖定准 , 张昌林 , 杨峥 , 李田 . 子宫颈鳞状上皮内病变中DHCR24蛋白的表达及其诊断价值[J]. 实用医学杂志, 2025 , 41(17) : 2748 -2754 . DOI: 10.3969/j.issn.1006-5725.2025.17.020
Objective To investigate the expression of Delta （24）-cholesteryl reductase （DHCR24） proteins in cervical squamous intraepithelial lesions （SILs） tissues and its value in different cervical lesion pathological diagnosis. Methods The expression of DHCR24， p16， and Ki-67 was quantitatively detected by immunohistochemistry in 51 normal cervical tissues， 44 LSILs， and 57 HSILs. The receiver operating characteristic （ROC） curve was drawn to analyze the diagnostic efficacy of DHCR24， p16， and Ki-67 proteins in evaluating the degree of SILs. Results The expression levels of DHCR24， p16 and Ki-67 protein were positively correlated with the progression of SILs （P < 0.05）. ROC analysis showed that the immunohistochemistry score cutoff value for DHCR24 between normal cervical tissue and LSIL was 0.1145， and between LSIL and HSIL was 0.1969. The sensitivity of DHCR24 in diagnosing LSIL was 79.55%， higher than that for p16 and Ki-67， which was 15.91% and 18.08%（P < 0.05）. The area under the ROC curve （AUC） for distinguishing normal cervical tissue from LSIL using a combination of DHCR24 and p16 was 0.932（95%CI：0.878 ~ 0.986）， higher than that for p16 and Ki-67 combined， which was 0.861（95%CI：0.785 ~ 0.936）. The AUC for distinguishing LSIL from HSIL using a combination of DHCR24 and p16 was0.971（95%CI：0.946 ~ 0.997）， higher than that for p16 and Ki-67 combined， which was 0.870（95%CI：0.790 ~ 0.949）. Conclusions Both DHCR24 and p16 protein expression levels can provide reference for the grading of SILs， and their combination can improve the diagnostic efficiency. The cutoff value derived from the ROC curve plotted by DHCR24 immunohistochemical staining intensity can improve the sensitivity of LSIL diagnosis.
| [1] | CASTLE P E， GAGE J C， WHEELER C M， et al. The clinical meaning of a cervical intraepithelial neoplasia grade 1 biopsy［J］. Obstet Gynecol， 2011， 118（6）：1222-1229. doi:10.1097/aog.0b013e318237caf4 |
| [2] | KURMAN R J， CARCANGIU M L， HERRINGTON C S， et al. WHO classification of tumors of female reproductive organs［M］. 4th ed，Lyon： IARC Press， 2014：121-154. doi:10.1007/978-1-4939-0779-3_112-1 |
| [3] | SIOKOS A G， SIOKOU-SIOVA O， TZAFETAS I. Correlation between cervical carcinogenesis and tobacco use by sexual partners［J］. Hell J Nucl Med， 2019， 22（2）：184-190. |
| [4] | SYKES P H， SIMCOCK B J， INNES C R， et al. Predicting regression of cervical intraepithelial neoplasia grade 2 in women under 25 years［J］. Am J Obstet Gynecol， 2022， 226（2）：222.e1-222.e13. doi:10.1016/j.ajog.2021.09.009 |
| [5] | CIAVATTINI A， DI GIUSEPPE J， MARCONI C， et al. Hysterectomy for cervical intraepithelial neoplasia： A retrospective observational multi-institutional study［J］. Int J Gynaecol Obstet， 2022， 159（3）：679-688. doi:10.1002/ijgo.14233 |
| [6] | 张清伟，尹如铁. 宫颈癌诊治热点与进展［J］. 实用医学杂志，2024，40（17）： 2357-2362． |
| [7] | TSOUMPOU I， ARBYN M， KYRGIOU M， et al. p16（INK4a） immunostaining in cytological and histological specimens from the uterine cervix： A systematic review and meta-analysis［J］. Cancer Treat Rev， 2009， 35（3）： 210-220. doi:10.1016/j.ctrv.2008.10.005 |
| [8] | SAMARAWARDANA P， SINGH M， SHROYER K R. Dual stain immunohistochemical localization of p16INK4A and ki-67： A synergistic approach to identify clinically significant cervical mucosal lesions［J］. Appl Immunohistochem Mol Morphol， 2011， 19（6）：514-518. doi:10.1097/pai.0b013e3182167c66 |
| [9] | ZHONG P， LI J， GU Y， et al. P16 and Ki-67 expression improves the diagnostic accuracy of cervical lesions but not predict persistent high risk human papillomavirus infection with CIN1［J］. Int J Clin Exp Pathol， 2015， 8（3）：2979-2986. |
| [10] | FUJII T， SAITO M， HASEGAWA T， et al. Performance of p16INK4a/Ki-67 immunocytochemistry for identifying CIN2+ in atypical squamous cells of undetermined significance and low-grade squamous intraepithelial lesion specimens： A Japanese Gynecologic Oncology Group study［J］. Int J Clin Oncol， 2015， 20（1）：134-142. doi:10.1007/s10147-014-0688-0 |
| [11] | 张波，杨志敏，康子婧，等. 子宫颈脱落细胞块联合p16/Ki?67双染在意义不明确的非典型鳞状上皮细胞和低级别鳞状上皮内病变的筛查意义［J］. 实用医学杂志，2022，38（22）： 2357-2362． |
| [12] | LUU W， ZERENTURK EJ， KRISTIANA I， et al. Signaling regulates activity of DHCR24， the final enzyme in cholesterol synthesis［J］. J Lipid Res， 2014， 55（3）：410-420. doi:10.1194/jlr.m043257 |
| [13] | Fu X， Wang Z. DHCR24 in Tumor Diagnosis and Treatment： A Comprehensive Review［J］. Technol Cancer Res Treat， 2024， 23：15330338241259780. doi:10.1177/15330338241259780 |
| [14] | DAI M， ZHU XL， LIU F， et al. Cholesterol synthetase DHCR24 induced by insulin aggravates cancer invasion and progesterone resistance in endometrial carcinoma［J］. Sci Rep， 2017， 7：41404. doi:10.1038/srep41404 |
| [15] | QIU T， CAO J， CHEN W， et al. 24-Dehydrocholesterol Reductase promotes the growth of breast cancer stem-like cells through the hedgehog pathway［J］. Cancer Sci， 2020， 111（10）：3653-3664. doi:10.1111/cas.14587 |
| [16] | ZHANG Y， WANG M， MENG F， et al. A novel SRSF3 inhibitor， SFI003， exerts anticancer activity against colorectal cancer by modulating the SRSF3/DHCR24/ROS axis［J］. Cell Death Discov， 2022， 8（1）：238. doi:10.1038/s41420-022-01039-9 |
| [17] | LI W， ZHANG C， GAO T， et al. Human umbilical cord mesenchymal stem cells small extracellular vesicles-derived miR-370-3p inhibits cervical precancerous lesions by targeting DHCR24［J］. Stem Cell Translat Med， 2024， 87：2157-6564. doi:10.1093/stcltm/szae087 |
| [18] | DALLA P P， GIORGI R P， COLLINA G， et al. The reproducibility of CIN diagnoses among different pathologists： Data from histology reviews from a multicenter randomized study［J］. Am J Clin Pathol， 2009， 132（1）：125-132. doi:10.1309/ajcpbrk7d1yiuwfp |
| [19] | DARRAGH T M， COLGAN T J， COX J T， et al. The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions： Background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology［J］. Arch Pathol Lab Med， 2012， 136（10）：1266-1297. |
| [20] | TRINGLER B， GUP C J， SINGH M， et al. Evaluation of p16INK4a and pRb expression in cervical squamous and glandular neoplasia［J］. Hum Pathol， 2004， 35（6）：689-696. doi:10.1016/j.humpath.2004.02.012 |
| [21] | SILVA D C， GON?ALVES A K， COBUCCI R N， et al. Immunohistochemical expression of p16， Ki-67 and p53 in cervical lesions-A systematic review［J］. Pathol Res Pract， 2017， 213（7）：723-729. doi:10.1016/j.prp.2017.03.003 |
| [22] | CHALOOB M K， HUSSEIN A G， QASIM B J. Correlation of P16 （Ink4a） and CK17 to HPV （16E6+18E6） in Premalignant and Malignant Lesions of Uterine Cervix： A Clinicopathologic Study［J］. Iran J Pathol， 2016， 11（4）：377-390. |
| [23] | R D P， ARUNACHALAM S， AMITKUMAR K， et al. An Immunohistochemical Study on Ki-67 Expression in Squamous Cell Carcinomas of Cervix With Clinicopathological Correlation［J］. Cureus， 2023， 15（1）：e34155. |
| [24] | SANGWAIYA A， GILL M， BAIRWA S， et al. Utility of P16/INK4a and Ki-67 in Preneoplasticand Neoplastic Lesions of Cervix［J］. Iran J Pathol， 2018， 13（3）：308-316. |
| [25] | MANDAL R， GHOSH I， BANERJEE D，et al. Correlation Between p16/Ki-67 Expression and the Grade of Cervical Intraepithelial Neoplasias［J］. Int J Gynecol Pathol， 2020， 39（4）：384-390. doi:10.1097/pgp.0000000000000617 |
| [26] | NEGRI G， BELLISANO G， CARICO E， et al. Usefulness of p16ink4a， ProEX C， and Ki-67 for the diagnosis of glandular dysplasia and adenocarcinoma of the cervix uteri［J］. Int J Gynecol Pathol， 2011， 30（4）：407-413. doi:10.1097/pgp.0b013e31820a79b0 |
| [27] | GREEVE I， HERMANS-BORGMEYER I， BRELLINGER C， et al. The human DIMINUTO/DWARF1 homolog seladin-1 confers resistance to Alzheimer's disease-associated neurodegeneration and oxidative stress［J］. J Neurosci， 2000， 20（19）：7345-7352. doi:10.1523/jneurosci.20-19-07345.2000 |
| [28] | YAN C， ZHENG L， JIANG S， et al. Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity［J］. Cancer Cell， 2023， 41（7）：1276-1293.e11. doi:10.1016/j.ccell.2023.04.016 |
| [29] | ERSHOV P， KALUZHSKIY L. Enzymes in the cholesterol synthesis pathway： Interactomics in the cancer context［J］. Biomedicines， 2021， 9（8）：895. doi:10.3390/biomedicines9080895 |
| [30] | CHIBAYA L， KARIM B， ZHANG H， et al. Mdm2 phosphorylation by Akt regulates the p53 response to oxidative stress to promote cell proliferation and tumorigenesis［J］. Proc Natl Acad Sci U S A， 2021， 118（4）：e2003193118. doi:10.1073/pnas.2003193118 |
| [31] | LIU X P， YIN X H， MENG X Y， et al. DHCR24 Predicts poor clinicopathological features of patients with bladder cancer： A STROBE-compliant study［J］. Medicine （Baltimore）， 2018， 97（39）：e11830. doi:10.1097/md.0000000000011830 |
| [32] | LEE G T， HA Y S， JUNG Y S， et al. DHCR24 Is an independent predictor of progression in patients with non-muscle-invasive urothelial carcinoma， and its functional role is involved in the aggressive properties of urothelial carcinoma cells［J］. Ann Surg Oncol， 2014， 21（）：S538-S545. doi:10.1245/s10434-014-3560-6 |
| [33] | SHUKLA A， SACHAN R， MAURYA M， et al. ROC-Analysis Derived Immunohistochemical P53 Cut-Off Scores as an Adjunct to Routine Histopathology for Better Diagnostic Compartmentalisation of Cervical Lesions［J］. Int J Appl Basic Med Res， 2022， 12（3）：177-184. doi:10.4103/ijabmr.ijabmr_416_21 |
/
| 〈 |
|
〉 |