Department of Nephrology, The Sixth People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai, 200233, China.
Physical Examination Center, Shanghai Lung Hospital Affiliated to Tongji University, Shanghai, 200433, China.
Sci Rep. 2023 Sep 21;13(1):15687. doi: 10.1038/s41598-023-42962-w.
Kidney renal clear cell carcinoma (KIRC) is the most prevalent type of kidney cancer and causes thousands of deaths each year. The prognosis for KIRC is poor. One critical factor is that the mechanism beneath KIRC is unclear. ORM1 is a reactant to acute inflammation. In this study, we demonstrated that methylation of ORM1 promoter was low and ORM1 was expressed significantly higher in KIRC. KIRC with higher ORM1 expression exhibited worse survival probability. Meanwhile, ORM1 was expressed higher in KIRC cell lines. When ORM1 was knocked down, cell proliferation ability was inhibited potently compared to the NC control. Cell migration as well as invasion ability were also suppressed dramatically. At molecular level, the expression of active caspase-3 and Bax was upregulated in ORM1-KD group while Bcl-2 downregulated. Moreover, CALR decreased following ORM1-KD and rescued expression of CALR increased Bcl-2 level but reduced the level of cleaved caspase-3 and Bax. Consistently, the apoptotic rate of 786-O and Caki-2 cells was upregulated in ORM1-KD but downregulated after CALR overexpression. The activity of caspase-3 was also regulated by ORM1-KD. In addition, the inhibition rate of sorafenib was enhanced in ORM1 KD group but reduced after overexpression of ORM1. Conclusively, ORM1 is clinically associated with progression of KIRC and regulates cell proliferation, migration, invasion, and apoptosis in KIRC. Moreover, ORM1 affects the efficiency of sorafenib in KIRC and regulates caspase-3 mediated cascades response through CALR molecule. This study provides us a new way to recognize the development and progression in KIRC.
肾透明细胞癌（KIRC）是最常见的肾癌类型，每年导致数千人死亡。KIRC 的预后较差。一个关键因素是 KIRC 背后的机制尚不清楚。ORM1 是急性炎症的反应物。在本研究中，我们证明了 ORM1 启动子的甲基化水平较低，KIRC 中 ORM1 的表达明显更高。ORM1 表达较高的 KIRC 表现出更差的生存概率。同时，KIRC 细胞系中 ORM1 的表达更高。当 ORM1 被敲低时，与 NC 对照相比，细胞增殖能力被强烈抑制。细胞迁移和侵袭能力也被显著抑制。在分子水平上，ORM1-KD 组中活性 caspase-3 和 Bax 的表达上调，而 Bcl-2 下调。此外，CALR 减少后，ORM1-KD 表达增加，CALR 增加 Bcl-2 水平，但降低 cleaved caspase-3 和 Bax 水平。此外，786-O 和 Caki-2 细胞的凋亡率在 ORM1-KD 中上调，但在 CALR 过表达后下调。ORM1-KD 还调节 caspase-3 的活性。此外，ORM1-KD 组中索拉非尼的抑制率增强，但 ORM1 过表达后降低。总之，ORM1 与 KIRC 的进展相关，并调节 KIRC 中的细胞增殖、迁移、侵袭和凋亡。此外，ORM1 通过 CALR 分子影响 KIRC 中索拉非尼的效率，并调节 caspase-3 介导的级联反应。本研究为我们提供了一种新的方法来认识 KIRC 的发展和进展。
