Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) S.A.S. Nagar, Sahibzada Ajit Singh Nagar, India.
Sci Rep. 2020 Oct 21;10(1):17954. doi: 10.1038/s41598-020-74847-7.
Breast cancer including triple negative breast cancer (TNBC) represents an important clinical challenge, as these tumours often develop resistance to conventional chemotherapeutics. MicroRNAs play a crucial role in cell-cycle regulation, differentiation, apoptosis, and migration. Herein, we performed Affymetrix Gene Chip miRNA 4.0 microarray and observed differential regulation of miRNAs (75 upregulated and 199 downregulated) in metastatic MDA-MB-231 cells as compared to immortalized human non-tumorigenic breast epithelial (MCF-10A) cells. MicroRNA-941 was significantly upregulated in MDA-MB-231 cells (almost nine-fold increase) in comparison to MCF-10A cells. Transfection of MiRNA-941 inhibitor significantly decreased the proliferation and migration of MDA-MB-231 cells by altering the expressions of p21, Cyclin D1, PP2B-B1, E-cadherin and MMP-13. Interestingly, we provide first evidence that inhibiting miR-941 prevents cell proliferation and phosphorylation of histone H3 at Ser10 residue. Xenograft model of breast cancer was developed by subcutaneous injection of MDA-MB-231 cells into the mammary fat pad of female athymic nude mice (Crl:NU-Foxn1nu). The tumours were allowed to grow to around 60 mm, thereafter which we divided the animals into seven groups (n = 5). Notably, intratumoral injection of miR-941 inhibitor significantly abolished the tumour growth in MDA-MB-231 xenograft model. 5-Fluorouracil (10 mg/kg, i.p.) was used as positive control in our study. To the best of our knowledge, we report for the first time that targeting miR-941 improves the sensitivity of MDA-MB-231 cells to 5-fluorouracil. This can be of profound clinical significance, as it provides novel therapeutic approach for treating variety of cancers (overexpressing miRNA-941) in general and breast cancers in particular.
乳腺癌，包括三阴性乳腺癌（TNBC），是一个重要的临床挑战，因为这些肿瘤常常对传统的化疗药物产生耐药性。miRNA 在细胞周期调控、分化、凋亡和迁移中起着至关重要的作用。在此，我们进行了 Affymetrix Gene Chip miRNA 4.0 微阵列分析，观察到转移性 MDA-MB-231 细胞与永生化的人非肿瘤性乳腺上皮（MCF-10A）细胞相比，miRNA 的差异表达（75 个上调和 199 个下调）。与 MCF-10A 细胞相比，miRNA-941 在 MDA-MB-231 细胞中显著上调（几乎增加了九倍）。转染 miRNA-941 抑制剂可通过改变 p21、Cyclin D1、PP2B-B1、E-cadherin 和 MMP-13 的表达，显著降低 MDA-MB-231 细胞的增殖和迁移。有趣的是，我们首次提供证据表明，抑制 miR-941 可防止细胞增殖和组蛋白 H3 在 Ser10 残基的磷酸化。我们通过将 MDA-MB-231 细胞皮下注射到雌性无胸腺裸鼠（Crl：NU-Foxn1nu）的乳腺脂肪垫中，建立了乳腺癌的异种移植模型。当肿瘤长到约 60mm 时，我们将动物分为七组（每组 5 只）。值得注意的是，miR-941 抑制剂的肿瘤内注射显著抑制了 MDA-MB-231 异种移植模型的肿瘤生长。我们的研究中，5-氟尿嘧啶（10mg/kg，腹腔注射）用作阳性对照。据我们所知，我们首次报道靶向 miR-941 可提高 MDA-MB-231 细胞对 5-氟尿嘧啶的敏感性。这具有深远的临床意义，因为它为治疗各种癌症（miRNA-941 过表达）提供了新的治疗方法，特别是乳腺癌。
