Qazvin University of Medical Sciences

Cytokeratins (CKs) are structural proteins vital to epithelial integrity and play key roles in breast cancer progression. This review explores their expression, functions, and therapeutic potential.

A systematic review was performed using PubMed, Scopus, and Google Scholar. We focused on in vivo, in vitro, and human studies - as well as review articles - published through 1982 that included keywords such as KRT5/13/16/17/18/19/23/80, Cytokeratin 5/13/16/17/18/19/23/80, Keratin 5/13/16/17/18/19/23/80, CK5/13/16/17/18/19/23/80, Cancer, Tumor, Breast cancer, Triple-negative breast cancer, and TNBC. Following title, abstract, and full-text screening of extracted studies, irrelevant articles and duplicates were excluded.

CK5 and CK17 are strongly associated with aggressive breast cancer subtypes, particularly triple-negative breast cancer (TNBC), influencing tumor invasiveness and drug resistance. CK18 and CK19 play key roles in estrogen receptor signaling and epithelial stability. Newly identified CKs, CK23 and CK80, show strong correlations with metastasis and poor prognosis. CK-driven pathways, such as the Wnt/β-catenin and EMT pathways, contribute to tumor progression and therapy resistance.

CKs are key biomarkers for breast cancer classification, prognosis, and therapy response. Their roles in tumor biology suggest potential for targeted treatment and personalized care to improve outcomes.

Statins were introduced as lipid-lowering agents that inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase; they are commonly administered to reduce cholesterol levels for cardioprotective purposes. Further studies suggested that statins have cholesterol-reducing-independent properties and exert pleiotropic therapeutic properties, including antioxidant, anti-inflammatory, anti-fibrotic, neuroprotective, and other beneficial effects. Adhesion molecules, including selectins, integrins, cadherins, CD44, and the immunoglobulin superfamily (IgSF) members, are essential mediators for those biological functions. The current review discusses studies performed in in vitro and in vivo in physiological and pathological models focusing on adhesion molecules such as Lymphocyte function-associated antigen-1 (LFA-1), macrophage-1 antigen (Mac-1), P-selectin, E-selectin, very late activation antigens-4 (VLA-4), and nectins that are therapeutically targeted by different types of statins and that highlight the potential therapeutic utility of statins for diseases other than cardiovascular disease.

Metformin induces radiation sensitivity in cancer cells, including colorectal cancer cells; however, the exact molecular mechanisms underlying its radiosensitive effects are not yet known. In this study, we investigated the role of the p53/miR-34a/SIRT1 pathway in the radiosensitivity of colon cancer cells.

The study was carried out from 2020 to 2022 at the Qazvin University of Medical Science's Cellular and Molecular Research Center. Two colorectal cancer cell lines (SW480 and SW620) obtained from primary and secondary tumors derived from a single patient were used as the study samples. After subjecting the cells to 50 Gy of radiation, we generated radioresistant cell lines. Resistant cells were treated with 50 μM metformin. Metformin-treated and untreated resistant cells constituted the study groups. The expression levels of miR-34-a and Sirtunin1 (SIRT1) were evaluated using Quantitative Real-time PCR. The rates of cell proliferation and apoptosis were assessed using a Cell Counting Kit-8 (CCK-8) assay and flow cytometry. Western blot analysis was performed to quantify the expression of proteins. For statistical analysis, the Student's ttest was carried out to examine the mean differences between the two groups, and analysis of variance (ANOVA) was used to examine additional groups.

Our results showed that the expression of miR-34-a was downregulated (0.29 ± 0.11) in radiation-resistant cancer cells (P <0.001), while the expression of SIRT-1 was upregulated (4.5 ± 0.25) (P <0.001). Metformin increased the radiosensitivity of colon cancer cells in a time- and dose-dependent manner. Treatment with 50 μM metformin after 48h caused decreased cell viability and increased apoptosis in resistant cells. We observed downregulation of SIRT-1 (1.1 ± 0.45) and upregulation of miR-34-a (4.3 ± 1.3) (P <0.001) in metformin-treated cells. In contrast, western blotting results showed the upregulation of acetylated P53 in metformin-treated cells. Metformin function was reversed by SIRT1 inhibitors or by transfection with miR-34-a overexpressing plasmids.

Based on these results, one of the radiosensitivity mechanisms of metformin in colorectal cancer is the modulation of the p53/miR-34a/SIRT1 loop.