Barsoum Farida S, Awad Amany S, Hussein Nada H, Eissa Reda A, El Tayebi Hend M
Molecular Pharmacology Research Group, Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt.
Department of Surgery, Ain Shams University, Egypt.
Pathol Res Pract. 2020 Dec;216(12):153274. doi: 10.1016/j.prp.2020.153274. Epub 2020 Nov 4.
Breast cancer (BC) remains a major health problem, despite the remarkable advances in cancer research setting. BC is the most common cancer affecting women worldwide. In the context of triple negative breast cancer (TNBC) treatment, major obstacles include late diagnoses and detrimental side effects of chemotherapy and radiotherapy. Research effort was rewarded with the discovery of mesothelin (MSLN), an oncogenic Glycosyl-Phosphatidyl-Inositol (GPI) anchored protein, over-expressed in TNBC. GPI pathway is a post-translational modification that attaches proteins to cellular membrane. MSLN targeted therapy succeeded in early clinical trials, nevertheless, to date, the epigenetic regulation of MSLN and GPI pathway by non-coding RNAs (nc-RNAs) in BC remains an untouched area. Accordingly, our aim is to investigate-for the first time- the impact of simultaneous targeting of MSLN and its associated GPI pathway member, PIG-C, by non-coding-RNAs. Expression profiling of PIG-C, MSLN in BC was performed. Using bioinformatics tools, MALAT-1 and miR-182 were found to target MSLN and PIG-C. MDA-MB-231 cells were transfected with synthetic nc-RNAs. Expression profiling of MSLN, miR-182 and MALAT-1 showed a dramatic over-expression in BC samples. MiR-182 ectopic expression and MALAT-1 silencing increased MSLN and PIG-C transcript levels. However, miR-182 inhibition and miR-182/si-MALAT-1 co-transfection lowered MSLN and PIG-C levels. Finally, si-PIG-C decreased MSLN and PIG-C levels. To conclude, our investigation unravels a new axis in TNBC, where miR-182 can manipulate MSLN and PIG-C. Meanwhile, MALAT-1 is the culprit lncRNA in this novel axis, possibly a sponge for miR-182. Altogether, this sheds light on new targets for BC immune-therapy.
尽管癌症研究领域取得了显著进展，但乳腺癌（BC）仍然是一个重大的健康问题。BC是全球影响女性的最常见癌症。在三阴性乳腺癌（TNBC）治疗方面，主要障碍包括诊断延迟以及化疗和放疗的有害副作用。间皮素（MSLN）的发现为研究工作带来了回报，MSLN是一种致癌的糖基磷脂酰肌醇（GPI）锚定蛋白，在TNBC中过表达。GPI途径是一种将蛋白质附着到细胞膜上的翻译后修饰。MSLN靶向治疗在早期临床试验中取得了成功，然而，迄今为止，BC中非编码RNA（nc-RNAs）对MSLN和GPI途径的表观遗传调控仍是一个未被触及的领域。因此，我们的目标是首次研究非编码RNA同时靶向MSLN及其相关的GPI途径成员PIG-C的影响。对BC中PIG-C、MSLN进行了表达谱分析。使用生物信息学工具发现，MALAT-1和miR-182靶向MSLN和PIG-C。用合成的nc-RNAs转染MDA-MB-231细胞。MSLN、miR-182和MALAT-1的表达谱显示在BC样本中显著过表达。miR-182异位表达和MALAT-1沉默增加了MSLN和PIG-C转录水平。然而，miR-182抑制以及miR-182/si-MALAT-1共转染降低了MSLN和PIG-C水平。最后，si-PIG-C降低了MSLN和PIG-C水平。总之，我们的研究揭示了TNBC中的一个新轴，其中miR-182可以调控MSLN和PIG-C。同时，MALAT-1是这个新轴中的罪魁祸首lncRNA，可能是miR-182的海绵。这一切都为BC免疫治疗的新靶点提供了线索。
