Rienzo Monica, Sorrentino Anna, Di Zazzo Erika, Di Donato Marzia, Carafa Vincenzo, Marino Maria Michela, De Rosa Caterina, Gazzerro Patrizia, Castoria Gabriella, Altucci Lucia, Casamassimi Amelia, Abbondanza Ciro
Department of Environmental, Biological, and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy.
Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
Front Oncol. 2021 Jan 29;10:583533. doi: 10.3389/fonc.2020.583533. eCollection 2020.
Positive Regulatory Domain (PRDM) gene family members commonly express two main molecular variants, the PR- isoform usually acting as tumor suppressor and the PR- one functioning as oncogene. Accordingly, PRDM2/RIZ encodes for RIZ1 (PR-) and RIZ2 (PR-). In human cancers, genetic or epigenetic modifications induce RIZ1 silencing with an expression level imbalance in favor of RIZ2 that could be relevant for tumorigenesis. Additionally, in estrogen target cells and tissues, estradiol increases RIZ2 expression level with concurrent increase of cell proliferation and survival. Several attempts to study RIZ2 function in HeLa or MCF-7 cells by its over-expression were unsuccessful. Thus, we over-expressed RIZ2 in HEK-293 cells, which are both RIZ1 and RIZ2 positive but unresponsive to estrogens. The forced RIZ2 expression increased cell viability and growth, prompted the G2-to-M phase transition and organoids formation. Accordingly, microarray analysis revealed that RIZ2 regulates several genes involved in mitosis. Consistently, RIZ silencing in both estrogen-responsive MCF-7 and -unresponsive MDA-MB-231 cells induced a reduction of cell proliferation and an increase of apoptosis rate. Our findings add novel insights on the putative RIZ2 tumor-promoting functions, although additional attempts are warranted to depict the underlying molecular mechanism.
正调控结构域（PRDM）基因家族成员通常表达两种主要的分子变体，PR-异构体通常作为肿瘤抑制因子起作用，而PR-异构体则发挥癌基因的功能。因此，PRDM2/RIZ编码RIZ1（PR-）和RIZ2（PR-）。在人类癌症中，基因或表观遗传修饰会导致RIZ1沉默，使表达水平失衡，有利于RIZ2，这可能与肿瘤发生有关。此外，在雌激素靶细胞和组织中，雌二醇会增加RIZ2的表达水平，同时细胞增殖和存活率也会增加。通过过表达在HeLa或MCF-7细胞中研究RIZ2功能的几次尝试均未成功。因此，我们在HEK-293细胞中过表达RIZ2，HEK-293细胞同时表达RIZ1和RIZ2，但对雌激素无反应。强制表达RIZ2可提高细胞活力和生长，促使细胞从G2期向M期转变并形成类器官。相应地，微阵列分析显示RIZ2调节几个参与有丝分裂的基因。同样，在雌激素反应性MCF-7细胞和非反应性MDA-MB-231细胞中沉默RIZ均会导致细胞增殖减少和凋亡率增加。我们的研究结果为RIZ2假定的促肿瘤功能提供了新的见解，尽管还需要进一步尝试来描述其潜在的分子机制。
