Ferraresi Alessandra, Ghezzi Ian, Salwa Amreen, Lualdi Chiara, Dhanasekaran Danny N, Isidoro Ciro
Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy.
Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Cells. 2025 May 22;14(11):765. doi: 10.3390/cells14110765.
NKX3-2, a transcriptional repressor factor belonging to the NK family of homeobox-containing proteins, has been widely studied for its role in promoting chondrogenic differentiation and homeostasis. NKX3-2 is upregulated in chemoresistant ovarian tumors and metastatic gastric cancer cells; however, its prognostic role and mechanistic involvement in cancer cell biology remain to be elucidated. By interrogating the TCGA database, we found that cancer patients with high - expression had a shorter overall survival rate than patients with low expression. In ovarian cancer patients, NKX3-2 negatively correlates with P53. Given the prominent role of the latter oncosuppressor in controlling DNA repair and cell death, here we investigate the molecular mechanism involved in this negative correlation in several ovarian cancer cell lines expressing different levels of the two proteins. We found that the high expression of endogenous or ectopic P53 reduced NKX3-2 protein expression, while its knockdown increased it. In contrast, the genetic manipulation of NKX3-2 expression did not affect P53 expression. Mechanistically, P53-mediated downregulation of NKX3-2 does not entail transcriptional activity or proteasomal clearance but occurs via P53-NKX3-2 protein-protein interaction, which in turn results in P53-induced NKX3-2 degradation via the autophagy-lysosome pathway. Remarkably, patients bearing a tumor characterized by low and high expression (indicative of active autophagy) display a better prognosis. Taken together, our data indicate that NKX3-2 represents a negative prognostic factor under P53 control in ovarian cancer. From a translational point of view, identifying this novel mechanism may represent a new molecular signature capable of predicting the clinical outcome of patients, a crucial aspect of developing personalized therapeutic approaches.
NKX3-2是一种属于含同源框蛋白NK家族的转录抑制因子，因其在促进软骨形成分化和内环境稳定中的作用而受到广泛研究。NKX3-2在化疗耐药的卵巢肿瘤和转移性胃癌细胞中上调；然而，其在癌症生物学中的预后作用和机制仍有待阐明。通过查询TCGA数据库，我们发现高表达的癌症患者总生存率低于低表达患者。在卵巢癌患者中，NKX3-2与P53呈负相关。鉴于后者这种肿瘤抑制因子在控制DNA修复和细胞死亡方面的突出作用，我们在此研究了几种表达不同水平这两种蛋白的卵巢癌细胞系中这种负相关所涉及的分子机制。我们发现内源性或异位P53的高表达降低了NKX3-2蛋白表达，而其敲低则增加了该表达。相反，NKX3-2表达的基因操作不影响P53表达。从机制上讲，P53介导的NKX3-2下调并不需要转录活性或蛋白酶体清除，而是通过P53-NKX3-2蛋白-蛋白相互作用发生，这反过来又导致P53通过自噬-溶酶体途径诱导NKX3-2降解。值得注意的是，肿瘤中低表达和高表达（表明自噬活跃）的患者预后较好。综上所述，我们的数据表明NKX3-2是卵巢癌中P53控制下的一个负性预后因子。从转化医学的角度来看，识别这一新机制可能代表一种能够预测患者临床结局的新分子特征，这是开发个性化治疗方法的一个关键方面。
