新长链非编码RNA LncRNA-RP4HA通过CAPRIN2/HMGCS1调控鼻咽癌转移与铁死亡

LncRNAs (long noncoding RNAs) are key regulators of tumorigenesis and progression. However, the function of lncRNAs in the metastasis and ferroptosis in nasopharyngeal carcinoma (NPC) remains to be identified. We recently found that long noncoding RNA regulated by P4HA1 (LncRNA-RP4HA) may play a vital role in NPC metastasis and ferroptosis. In this study, we will prove that LncRNA-RP4HA promotes NPC cells migration in vitro and metastasis in vivo through CAPRIN2 / HMGCS1 axis. Moreover, LncRNA-RP4HA protects against ferroptosis in NPC by activating CAPRIN2 / HMGCS1. Therefore, LncRNA-RP4HA can be used as a prognostic indicator and potential therapeutic target of NPC. In addition, we set out to construct a novel minicircle therapeutic system (mc-oriP-shRP4HA) in which the LncRNA-RP4HA shRNA expression was mediated by minicircle DNA vector. mc-oriP-shRP4HA will be tested for its inhibition effects on tumor metastasis and promotion effects on ferroptosis. This study reveals that LncRNA-RP4HA / CAPRIN2 / HMGCS1 axis constitutes a novel mechanism of NPC metastasis and ferroptosis, which will lay the foundation for targeted therapy of NPC.

LncRNA（long noncoding RNA）是肿瘤发生、发展过程中不可或缺的重要调控因子。然而，lncRNA在鼻咽癌转移和铁死亡中的作用目前仍很不清楚。我们的前期研究发现，新长链非编码RNA LncRNA-RP4HA（LncRNA Regulated by P4HA1）是鼻咽癌转移和铁死亡的重要调控分子。本研究将深层次解析LncRNA-RP4HA促进转移、抑制铁死亡的分子机制，证明其通过激活CAPRIN2 / HMGCS1轴而起作用，可以作为鼻咽癌的预后预测指标及治疗的新靶点。我们将利用鼻咽癌靶向的新型小环载体系统，特异性表达shRNA，以下调LncRNA-RP4HA，进而抑制鼻咽癌转移、促进铁死亡。本项目将阐明LncRNA-RP4HA / CAPRIN2 / HMGCS1轴调控鼻咽癌转移和铁死亡的作用和机制，为鼻咽癌的治疗提供新的候选药物。

长链非编码RNA（lncRNA, long noncoding RNA）是肿瘤发生、发展过程中不可或缺的重要调控因子。迄今为止，对于lncRNA在鼻咽癌转移和铁死亡中的功能与作用机制仍知之甚少。本项目致力于发现在表观层面对鼻咽癌转移和铁死亡进行调控的lncRNA分子。研究结果表明，受P4HA1激活的长链非编码RNA（LncRNA Regulated by P4HA1，LncRNA-RP4HA），即LINC00941，在促进鼻咽癌转移和铁死亡抵抗中发挥重要作用。进一步的机制研究发现，LINC00941的靶分子是RNA结合蛋白CAPRIN2，而甲羟戊酸（mevalonate, MVA）通路是CAPRIN2下游的重要效应通路。MVA通路的关键酶HMGCS1与HMGCR通过催化MVA的生成，调控细胞代谢与抗氧化防御。补充MVA可部分逆转敲降CAPRIN2对细胞迁移、侵袭、ECM脱离存活与铁死亡的调控作用。P4HA1、LINC00941与CAPRIN2通过调控MVA通路关键酶（HMGCS1与HMGCR）激活细胞抗氧化防御系统，降低胞内ROS水平，抑制氧化应激，促进ECM脱离细胞存活、促进体内转移，保护肿瘤细胞免于铁死亡。P4HA1、LINC00941及CAPRIN2与鼻咽癌的进展转移密切相关。利用鼻咽癌靶向的新型小环载体系统，特异性表达靶向该lncRNA的shRNA，可抑制鼻咽癌细胞迁移、侵袭、ECM脱离存活与转移，并且导致细胞对铁死亡敏感。综上所述，本研究发现了新的鼻咽癌预后预测指标、铁死亡敏感标志物及治疗靶点，有望为鼻咽癌的治疗提供新的候选药物。