Expression of Ki67 in Precancerous Squamous Cell Skin Lesion of Mice Induced by DMBA

Siti Nurkasanah, Aida S D Hoemardani, Evlina Suzanna Sinuraya


Background: Squamous cell carcinoma (SCC) is an invasive skin cancer that is found in the human skin. SCC growth from the precancerous lesion is known as a wart or papilloma. Ki67 is a protein expressed by cells during proliferation. Cells with higher Ki67 expression showed abnormal regulation of apoptosis. 5-FU is an antimetabolite compound that works as a DNA/RNA pyrimidine antagonist molecule that can induce cell apoptosis. The main objective of this research is to evaluate the inhibition proliferation of precancerous squamous cell in skin lesion induced by DMBA/croton oil treated by using 5-FU cream topically compared to 5% imiquimod cream.

Methods: This research assesses three different concentrations of 5-FU cream namely 1%, 2%, and 5% topically on 24 wild type mice divided into 6 groups of 4 each including positive control (with carcinogenesis but without treatment), negative control (without treatment ; normal), carcinogenesis with treatment 5-FU cream (1%, 2%, and 5%) or 5% imiquimod cream. The expression of Ki67 was analyzed using immunohistochemistry. Statistical analysis was performed by one-way ANOVA using SPSS version 23.

Results: Based on this research, 5-FU cream treatment during 4 weeks (week 10-week 14) showed the decrease of cumulative number of papilloma (p<0.05) and immunohistochemistry analysis resulted in the lowest Ki67 expression in 5-FU 2% and 5% groups compared to 5% imiquimod cream (p<0.05).

Conclusions: 5-FU cream treatment during 4 weeks showed a decrease of papilloma and Ki67 expression in 5-FU cream 2% and


fluorouracil, Ki67, squamous cell precancerous, skin, topical treatment


Netscher D, Leong M, Orengo I, et al. Cutaneous malignancies: melanoma and nonmelanoma types. PlastReconstr Surg. 2011;127(3):37e-56e.

Singh M, Suman S, Shukla Y. New enlightenment of skin cancer chemoprevention through phytochemicals: In vitro and in vivo studies and the underlying mechanisms. Biomed Res Int. 2014;10(4):1–18.

Li LT, Jiang G, Chen Q, Zheng JN. Predic Ki67 is a promising molecular target in the diagnosis of cancer (Review). Mol Med Rep. 2015;11(3):1566–72.

Prihantono P, Muchamad H, Critian B, Daniel S, Haryasen H, Berti N, et al. Ki67 expression by immunohistochemistry and quantitative real time polymerase chain reaction asa predictor of clinical response to neoadjuvant chemotherapy in locally advanced breast cancer. J. Oncol. 2017;2017: 1-8.

Ceilley RI. Mechanisms of action of topical 5- fluorouracil : Review and implications for the treatment of dermatological disorders. J Dermatolog Treat. 2012;23(2):83–9.

Zhang N, Yin Y, Xu S-J, Chen W-S. 5-Fluorouracil: Mechanisms of Resistance and Reversal Strategies. Molecules. 2008;13(8):1551–69.

Chinembiri TN, Gerber M, Plessis L, Preez J, Plessis J. Topical Delivery of 5-Fluorouracil from Pheroid TM Formulations and the In Vitro Efficacy Against Human Melanoma.AAPS PharmSciTech.2015;16(6):1390–9.

Sati J, Mohanty BP, Garg ML, Koul A. Pro-Oxidant role of silibinin in DMBA/TPA Induced Skin Cancer: 1H NMR metabolomic and biochemical study. PLoS One. 2016;11(7):1–23.

Qiblawi S, Dhanarasu S. Chemopreventive potential of fish oil against 7 , 12-dimethyl benz ( a ) anthracene and croton oil induced two-stage mouse skin. Biomed Res. 2017;28(6):2596–603.

Arora N, Koul A, Bansal MP. Chemopreventive activity of Azadirachtaindica on two-stage skin carcinogenesis in murine model. Phyther Res. 2011;25(3):408–16.

Sharma J, Goyal PK. Chemoprevention of chemical-induced skin cancer by Panaxginsenroot extract. J Ginseng Res. 2015;39(3):265–73.

Abel EL, Angel JM, Kiguchi K, Digiovanni J. Multi-stage chemical carcinogenesis in mouse skin: Fundamentals and applications. Nat Protoc. 2011;4(9):1350–62.

Nassar D, Latil M, Boeckx B, Lambrechts D, Blanpain C. Genomic landscape of carcinogen-induced and genetically induced mouse skin squamous cell carcinoma. Nat Med. 2015;21(8):946–54.

Subramanian V, Venkatesan B, Tumala A, Vellaichamy E. Topical application of Gallic acid suppresses the 7 , 12-DMBA / Croton oil induced two-step skin carcinogenesis by modulating anti-oxidants and MMP-2 / MMP-9 in Swiss albino mice. Food ChemToxicol. 2014;66:44–5.

Rowert-Huber J, Patel MJ, Forshner T, Ulrich C, Eberle J, Kerl H, et al. Actinic keratosis is an early in situ squamous cell carcinoma: a proposal for reclassification. Br J Dermatol;156(3):8-12

Gu J, Ren L, Wang X, Qu C, Zhang Y. Expression of livin , survivin and caspase-3 in prostatic cancer and their clinical significance. Int J Clin Exp Pathol. 2015;8(11):14034–9.

Li LT, Jiang G, Chen Q, Zheng JN. Predic Ki67 is a promising molecular target in the diagnosis of cancer (Review). Mol Med Rep. 2015;11(3):1566–72.

Deniz F, Dilek K, Hande M, Umit UM, Handan K. Ki-67 and caspase expression in breast carcinoma: Does variance in locational sampling exist? Int J Clin Exp Pathol. 2015;8(9):11305–13.

Berdjis N, Meye A, Nippgen J, Dittert D, Hakenberg O, Baretton GB, et al. Expression of Ki-67 in squamous cell carcinoma of the penis. BJU Int. 2005;96(1):146–8.

Coutinho-Camillo CM, Lourenço SV, Puga RD, Damascena AS, Teshima THN, Kowalski LP, et al. Profile of apoptotic proteins in oral squamous cell carcinoma: A cluster analysis of 171 cases. Appl Cancer Res. 2017;37(1):2.

Full Text: PDF

DOI: 10.33371/ijoc.v13i2.638

Article Metrics

Abstract view : 118 times
PDF - 121 times


  • There are currently no refbacks.

Copyright (c) 2019 Indonesian Journal of Cancer

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.