Nanjing Medical University Affiliated Cancer Hospital and Research Center for Clinical Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, 42 BaiZiTing Road, Nanjing, Jiangsu, 210000, People's Republic of China.
Jiangsu Provincial Institute of Materia Medica, Nanjing Tech University, Nanjing, Jiangsu, China.
Funct Integr Genomics. 2023 Sep 2;23(3):290. doi: 10.1007/s10142-023-01208-8.
Clk4-associated serine/arginine-rich protein (CLASRP), an alternative splicing regulator, may be involved in the development and progression of cancer by regulating the activity of the CDC-like kinase (Clk) family. This study explored the biological function of CLASRP in colorectal cancer (CRC). The expression of CLASRP, which is associated with clinicopathological features, was analysed in CRC tissues and paired noncancer tissues by RT-PCR. The roles of CLASRP were investigated in CRC cells transfected with plasmids or shRNA through proliferation, migration and invasion assays in vitro and a xenograft model in vivo. Apoptosis was analysed using CLASRP-overexpressing CRC cells by western blotting. Clk inhibitors were used to perform functional research on CLASRP in CLASRP-overexpressing CRC cells. CLASRP was significantly upregulated in CRC cell lines, while high CLASRP expression was correlated with metastasis in CRC patients. Functionally, overexpression of CLASRP significantly promoted the proliferation, migration and invasion of CRC cells in vitro and tumour growth in vivo. Mechanistically, the proliferation, migration and invasion of CLASRP-overexpressing CRC cells were inhibited by Clk inhibitors, accompanied by low expression of CLASRP at the gene and protein levels. Clk inhibitors induced apoptosis of CLASRP-overexpressing CRC cells, resulting in direct blockade of cell growth. The expression levels of cleaved caspase 3 and cleaved caspase 8 were increased in CLASRP-overexpressing CRC cells treated with Clk inhibitors. CLASRP might serve as a promotional oncogene in CRC cells and be suppressed by Clk inhibitors through activation of caspase pathways.
CLK4 相关丝氨酸/精氨酸丰富蛋白（CLASRP）作为一种可变剪接调控因子，可能通过调节 CDC 样激酶（Clk）家族的活性，参与癌症的发生和发展。本研究探讨了 CLASRP 在结直肠癌（CRC）中的生物学功能。通过 RT-PCR 分析 CRC 组织和配对非癌组织中与临床病理特征相关的 CLASRP 表达。通过体外增殖、迁移和侵袭实验以及体内异种移植模型，研究了转染质粒或 shRNA 的 CRC 细胞中 CLASRP 的作用。通过 Western blot 分析 CLASRP 过表达 CRC 细胞的凋亡。使用 Clk 抑制剂在 CLASRP 过表达的 CRC 细胞中进行 CLASRP 的功能研究。CLASRP 在 CRC 细胞系中明显上调，而 CRC 患者中高 CLASRP 表达与转移相关。功能上，CLASRP 的过表达显著促进 CRC 细胞在体外的增殖、迁移和侵袭以及体内肿瘤生长。机制上，Clk 抑制剂抑制 CLASRP 过表达 CRC 细胞的增殖、迁移和侵袭，同时伴随基因和蛋白水平上 CLASRP 的低表达。Clk 抑制剂诱导 CLASRP 过表达 CRC 细胞凋亡，导致细胞生长直接受阻。CLASRP 过表达 CRC 细胞中 cleaved caspase 3 和 cleaved caspase 8 的表达水平增加。CLASRP 可能作为 CRC 细胞中的促进癌基因，并通过激活 caspase 途径被 Clk 抑制剂抑制。
