Expression and significance of cyclin D1, cyclin-dependent kinase 4 and cyclin-dependent kinase inhibitor P27 in patients with non-neoplastic epithelial disorders of the vulva

Liu,Huamei; Zhang,Fan; Li,Zongheng

doi:10.3892/etm.2023.12055

Expression and significance of cyclin D1, cyclin-dependent kinase 4 and cyclin-dependent kinase inhibitor P27 in patients with non-neoplastic epithelial disorders of the vulva

Authors:
- Huamei Liu
- Fan Zhang
- Zongheng Li
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Affiliations: Department of Gynecology and Obstetrics, Xiangyang Hospital of Integrated Chinese and Western Medicine, Xiangyang, Hubei 441000, P.R. China, Department of Gynecology and Obstetrics, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
Published online on: June 2, 2023 https://doi.org/10.3892/etm.2023.12055
Article Number: 356

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Abstract

Non-neoplastic epithelial disorders of the vulva (NNEDV) are prevalent and refractory gynecological diseases. However, the underlying pathogenesis of these diseases remain unclear. The present study aimed to investigate the expression and significance of cyclin D1, cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase inhibitor P27 (P27) in patients with NNEDV and provide a reference for clinical diagnosis and treatment. Normal vulvar skin samples from patients with perineum repair (control group, n=20) and skin samples from the vulvar lesions of patients with NNEDV (NNEDV group, n=36) were collected. Expression levels of cyclin D1, CDK4 and P27 were assessed in the samples using immunohistochemistry. The expression of each protein was evaluated based on the mean optical density (MOD). The MODs of cyclin D1 and CDK4 were significantly higher in samples of the three pathological types of NNEDV, namely squamous hyperplasia (SH), lichen sclerosus (LS) and mixed SH and LS lesions, compared with those of the control group. The MOD of P27 was lower in samples of the three pathological types of NNEDV than in the control group, although the difference was not statistically significant. No significant differences in the MOD of cyclin D1, CDK4 and P27 were detected among the three pathological types of NNEDV. The ratios of the MOD of cyclin D1 and CDK4 in the prickle cell layer to those in the basal cell layer were significantly higher in the NNEDV group than in the control group. However, the ratio of the MOD of P27 in the prickle cell layer to that in the basal cell layer exhibited no significant difference between the NNEDV and control groups. NNEDV has the potential for malignant transformation. The occurrence and development of NNEDV may be associated with the acceleration of cell proliferation, in which cyclin D1, CDK4 and P27 contribute to regulation of the cell cycle. Therefore, cyclin D1, CDK4 and P27 may be potential targets in the development of new clinical therapeutic drugs for patients with NNEDV.

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1	Nieuwenhof H, Avoort I and Hullu J: Review of squamous premalignant vulvar lesions. Crit Rev Oncol Hematol. 68:131–156. 2008.PubMed/NCBI View Article : Google Scholar
2	Ruan L, Xie Z, Wang H, Jiang J, Shi H and Xu J: High-intensity focused ultrasound treatment for non-neoplastic epithelial disorders of the vulva. Int J Gynecol Obstet. 109:167–170. 2010.PubMed/NCBI View Article : Google Scholar
3	Pu D and Hou M: Etiology and pathogenesis of white lesions of the vulva. J Practical Obstetrics Gynecol. 19:2–3. 2003.(In Chinese).
4	Li GT, Cao JH and Fu YJ: Expression of cyclin D1 and p16 protein in vulvar white lesion. Zhonghua Fu Chan Ke Za Zhi. 41:322–325. 2006.PubMed/NCBI(In Chinese).
5	Bantie L, Tadesse S, Likisa J, Yu M, Noll B, Heinemann G, Lokman NA, Ricciardelli C, Oehler MK, Beck A, et al: A first-in-class CDK4 inhibitor demonstrates in vitro, ex-vivo and in vivo efficacy against ovarian cancer. Gynecol Oncol. 159:827–838. 2020.PubMed/NCBI View Article : Google Scholar
6	Le J: Gynecology and Obstetrics (7th edition). People's Health Publishing House. 231-235:2008.(In Chinese).
7	Hartwell L H, Culotti J, Pringle JR and Reid BJ: Genetic control of the cell division cycle in yeast: A model to account for the order of cell cycle events is deduced from the phenotypes of yeast mutants. Science. 183:46–51. 1974.
8	Frederick TJ and Wood TL: IGF-I and FGF-2 coordinately enhance cyclin D1 and cyclin E-cdk2 association and activity to promote G1 progression in oligodendrocyte progenitor cells. Mol Cell Neurosci. 25:480–492. 2004.PubMed/NCBI View Article : Google Scholar
9	Du Q, Guo X, Wang M, Li Y, Sun X and Li Q: The application and prospect of CDK4/6 inhibitors in malignant solid tumors. J Hematol Oncol. 13(41)2020.PubMed/NCBI View Article : Google Scholar
10	Qie S and Diehl JA: Cyclin D degradation by E3 ligases in cancer progression and treatment. Semin Cancer Biol. 67:159–170. 2020.PubMed/NCBI View Article : Google Scholar
11	Billard-Sandu C, Tao YG, Sablin MP, Dumitrescu G, Billard D and Deutsch E: CDK4/6 inhibitors in P16/HPV16-negative squamous cell carcinoma of the head and neck. Eur Arch Otorhinolaryngol. 277:1273–1280. 2020.PubMed/NCBI View Article : Google Scholar
12	Deng L, Xu M, Fu L, Du G and Wang L: Effects of CDK4/6 inhibitor palbociclib on proliferation, cell cycle and apoptosis of human melanoma cells. Tumor. 40:521–530. 2020.(In Chinese).
13	Liu J, Peng Y and Wei W: Cell cycle on the crossroad of tumorigenesis and cancer therapy. Trends Cell Biol. 32:30–44. 2022.PubMed/NCBI View Article : Google Scholar
14	Bury M, Le Calvé B, Ferbeyre G, Blank V and Lessard F: New insights into CDK regulators: Novel opportunities for cancer therapy. Trends Cell Biol. 31:331–344. 2021.PubMed/NCBI View Article : Google Scholar
15	Janumyan Y, Cui Q, Yan L, Sansam CG, Valentin M and Yang E: G0 function of BCL2 and BCL-xL requires BAX, BAK, and p27 phosphorylation by mirk, revealing a novel role of BAX and BAK in quiescence regulation. J Biol Chem. 283:34108–34120. 2008.PubMed/NCBI View Article : Google Scholar
16	Lee S, Kim S, Chung H, Moon JH, Kang SJ and Park CG: Mesenchymal stem cell-derived exosomes suppress proliferation of T cells by inducing cell cycle arrest through p27kip1/Cdk2 signaling. Immunol Lett. 225:16–22. 2020.PubMed/NCBI View Article : Google Scholar
17	Kalu NN and Johnson FM: Do CDK4/6 inhibitors have potential as targeted therapeutics for squamous cell cancers? Expert Opin Investig Drugs. 26:207–217. 2017.PubMed/NCBI View Article : Google Scholar
18	Zhou J, Wu Z, Wong G, Pectasides E, Nagaraja A, Stachler M, Zhang H, Chen T, Zhang H, Liu JB, et al: CDK4/6 or MAPK blockade enhances efficacy of EGFR inhibition in oesophageal squamous cell carcinoma. Nat Commun. 8(13897)2017.PubMed/NCBI View Article : Google Scholar
19	Fang L, Xu X, Zheng W, Wu L and Wan H: The expression of microRNA-340 and cyclin D1 and its relationship with the clinicopathological characteristics and prognosis of lung cancer. Asian J Surg. 44:1363–1369. 2021.PubMed/NCBI View Article : Google Scholar
20	Laisom A, Pukhrambam G, Shameen Y, Akoijam N and Sen R: Immunohistochemical study on pten and cyclin D1 in non-neoplastic and neoplastic endometrial lesions. Int J Med Biomed Studies. 5:2021.
21	Thambiah LJ, Bindushree RV, Anjum A, Pugazhendi SK, Babu L and Nair RP: Evaluating the expression of p16 and p27 in oral epithelial dysplasias and oral squamous cell carcinoma: A diagnostic marker for carcinogenesis. J Oral Maxillofac Pathol. 22:59–64. 2018.PubMed/NCBI View Article : Google Scholar
22	Kamai T, Takagi K, Asami H, Ito Y, Arai K and Yoshidal KI: Prognostic significance of p27Kip1 and Ki-67 expression in carcinoma of the renal pelvis and ureter. BJU Int. 86:14–19. 2000.PubMed/NCBI View Article : Google Scholar
23	Hao S, Wu X and Li H: Expression and significance of cyclin D1 in vulvar carcinogenesis. China Modern Doctor. 47:15–16. 2009.(In Chinese).
24	Yanagi T, Hata H, Mizuno E, Kitamura S, Imafuku K, Nakazato S, Wang L, Nishihara H, Tanaka S and Shimizu H: PCTAIRE1/CDK16/PCTK1 is overexpressed in cutaneous squamous cell carcinoma and regulates p27 stability and cell cycle. J Dermatol Sci. 86:149–157. 2017.PubMed/NCBI View Article : Google Scholar
25	Shi X, Zhu K, Ye Z and Yue J: VCP/p97 targets the nuclear export and degradation of p27Kip1 during G1 to S phase transition. FASEB J. 34:5193–5207. 2020.PubMed/NCBI View Article : Google Scholar
26	Li Y, Xiao X, Chen H, Chen Z, Hu K and Yin D: Transcription factor NFYA promotes G1/S cell cycle transition and cell proliferation by transactivating cyclin D1 and CDK4 in clear cell renal cell carcinoma. Am J Cancer Res. 10:2446–2463. 2020.PubMed/NCBI
27	Zhou L, Liu R, Liang X, Zhang S, Bi W, Yang M, He Y, Jin J, Li S, Yang X, et al: lncRNA RP11-624L4.1 is associated with unfavorable prognosis and promotes proliferation via the CDK4/6-cyclin D1-Rb-E2F1 pathway in NPC. Mol Ther Nucleic Acids. 22:1025–1039. 2020.PubMed/NCBI View Article : Google Scholar
28	Nawroth R, Koch J, Mantwill K, Hindupuhr S and Holm PS: CDK4/6 inhibitors improve therapy of oncolytic adenovirus by manipulation of RB-E2F regulated transcription. Urologic Oncol. 38:908–909. 2020.
29	Li W, Li Y, Wang Z, Ren H, Zhang Y, Yang P, Pan S and Wang Y: Genistein promotes the proliferation of ovarian cancer OVCAR-5 cells by upregulating cyclin D1 and CDK4 expressions. J Xian Jiaotong University (Medical Sciences). 42:59–64. 2021.PubMed/NCBI View Article : Google Scholar : (In Chinese).
30	Kagawa Y, Yoshida K, Hirai T and Toge T: Significance of the expression of p27Kip1 in esophageal squamous cell carcinomas. Dis Esophagus. 13:179–184. 2000.PubMed/NCBI View Article : Google Scholar
31	Zamparelli A, Masciullo V, Bovicelli A, Santini D, Ferrandina G, Minimo C, Terzano P, Costa S, Cinti C, Ceccarelli C, et al: Expression of cell-cycle -associated proteins pRB2/p130 and p27kip in vulvar squamous cell carcinomas. Hum Pathol. 32:4–9. 2001.PubMed/NCBI View Article : Google Scholar
32	Zannoni GF, Faraglia B, Tarquini E, Camerini A, Vrijens K, Migaldi M, Cittadini A and Sgambato A: Expression of the CDK inhibitor p27kip1 and oxidative DNA damage in non-neoplastic and neoplastic vulvar epithelial lesions. Mod Pathol. 19:504–513. 2006.PubMed/NCBI View Article : Google Scholar
33	Pu D, Yin L, Hu F and Li N: DNA content, PCNA and P53 expression vulve lichen sclerosus and their relation with cell proliferation. Chinese J Histochem Cytochem. 2:169–173. 2001.(In Chinese).
34	Liu H, Xue X, Su B and Zhang X: Expression and significance of EGFR a and anti-oncogene protein p53 in vulva dystrophy and carcinoma of old women. China J Modern Med. 7:4–7. 2004.(In Chinese).