Research Service, Minneapolis VA Health Care System, Minneapolis, MN, 55417, USA.
Minnesota Supercomputing Institute, University of Minnesota, 117 Pleasant Street Southeast, Minneapolis, MN, 55455, USA.
Mol Med. 2024 Oct 11;30(1):175. doi: 10.1186/s10020-024-00937-1.
Protein kinase CK2 is a ubiquitous and highly conserved protein Ser/Thr kinase with diverse cell functions. CK2 is upregulated in various cancers and affects numerous aspects of their underlying pathobiology. The important role of microRNAs (miRNAs) referred to as oncomirs is also recognized in various cancers. Elevation of both CK2 and altered miRNA expression in cancers raised the question whether there was a connection between CK2 function and oncomirs in cancer.
PCR array analysis was used to examine the effects of CK2 siRNA-mediated downregulation on miRNA levels in C4-2 prostate cancer cells. We employed prostate cancer, breast cancer, and head and neck squamous cell carcinoma (HNSCC) cells as well as a prostate cancer xenograft orthotopic tumor model to examine the effects of CK2 siRNA-mediated downregulation or chemical inhibition on oncomir cluster miR-17 ~ 92 and miR-106b ~ 25 constituent miRNAs by quantitative reverse-transcriptase stem-loop PCR. Pri-miRNAs were measured in cancer cell lines by quantitative reverse-transcriptase PCR. Protein levels were assessed by western blot. PC3-LN4 prostate cancer orthotopic xenograft tumors and blood were collected from nude mice following repeated treatments with tenfibgen ligand nanocapsules containing RNAi-CK2 or RNAi-Control cargoes.
PCR array analysis demonstrated effect on a subset of miRNAs following CK2 downregulation; we focused our investigation on CK2 regulation of miR-17 ~ 92 and 106b ~ 25 oncomir clusters. Chemical inhibition or molecular downregulation of CK2 greatly reduced expression of miR-17 ~ 92 and 106b ~ 25 in prostate, breast and head and neck cancer cells in vitro. CK2α and CK2α´ protein levels were significantly correlated with many of the miR-17 ~ 92 and some of the miR-106b ~ 25 constituent members in prostate cancer cells. Decreased pri-miRNA levels for the miR-17 ~ 92 gene cluster transcript were observed for 5 of 6 cancer cell lines tested following CK2 downregulation. Nanocapsule-mediated delivery of RNAi-CK2 reduced CK2 protein expression in orthotopic prostate xenograft tumors and decreased intra-tumoral and serum levels of the oncomirs.
Targeting CK2 for the development of new cancer therapies is under active investigation in many laboratories and pharmaceutical companies. Our data suggest a new role for CK2 in cell signaling and survival in multiple cancer types through maintenance of miR-17 ~ 92 and 106b ~ 25 biogenesis.
蛋白激酶 CK2 是一种普遍存在且高度保守的丝氨酸/苏氨酸激酶，具有多种细胞功能。CK2 在各种癌症中上调，并影响其潜在病理生物学的许多方面。微小 RNA（miRNA）也被称为癌基因 miRNA 的重要作用在各种癌症中得到了认可。癌症中 CK2 的升高和 miRNA 表达的改变提出了 CK2 功能与癌症中癌基因 miRNA 之间是否存在联系的问题。
采用 PCR 阵列分析研究 CK2 siRNA 介导的下调对 C4-2 前列腺癌细胞中 miRNA 水平的影响。我们使用前列腺癌、乳腺癌和头颈部鳞状细胞癌（HNSCC）细胞以及前列腺癌异种移植原位肿瘤模型，通过定量逆转录酶茎环 PCR 研究 CK2 siRNA 介导的下调或化学抑制对癌基因簇 miR-1792 和 miR-106b25 组成 miRNA 的影响。通过定量逆转录酶 PCR 在癌细胞系中测量 Pri-miRNA。通过 Western blot 评估蛋白水平。在接受含有 RNAi-CK2 或 RNAi-Control cargos 的 tenfibgen 配体纳米胶囊重复治疗后，从裸鼠的 PC3-LN4 前列腺癌原位异种移植肿瘤和血液中收集。
PCR 阵列分析显示 CK2 下调后对一组 miRNA 有影响；我们将研究重点放在 CK2 对 miR-1792 和 106b25 癌基因 miRNA 簇的调节上。化学抑制或 CK2 分子下调显著降低了体外前列腺癌、乳腺癌和头颈部癌症细胞中 miR-1792 和 106b25 的表达。CK2α 和 CK2α'蛋白水平与前列腺癌细胞中许多 miR-1792 和一些 miR-106b25 组成成员显著相关。在 6 种测试的癌细胞系中，miR-17~92 基因簇转录物的 Pri-miRNA 水平在 CK2 下调后降低了 5 种。纳米胶囊介导的 RNAi-CK2 递送至原位前列腺异种移植肿瘤中降低了 CK2 蛋白表达，并降低了肿瘤内和血清中的癌基因 miRNA。
许多实验室和制药公司正在积极研究针对 CK2 开发新的癌症治疗方法。我们的数据表明，CK2 通过维持 miR-1792 和 106b25 的生物发生，在多种癌症类型中通过细胞信号转导和存活发挥新的作用。
