Hu Guanghui, Huang Ning, Zhang Jing, Zhang Die, Wang Shuren, Zhang Yuanyuan, Wang Liming, Du Yingxi, Kuang Shuwen, Ma Kai, Zhu Hongxia, Xu Ningzhi, Liu Mei
Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Mol Carcinog. 2023 Nov;62(11):1659-1672. doi: 10.1002/mc.23606. Epub 2023 Jul 14.
Colorectal cancer (CRC) is one of the most common malignant tumors. Approximately 5%-6% of CRC cases are associated with hereditary CRC syndromes, including the Peutz-Jeghers syndrome (PJS). Liver kinase B1 (LKB1), also known as STK11, is the major gene responsible for PJS. LKB1 heterozygotic deficiency is involved in intestinal polyps in mice, while the mechanism of LKB1 in CRC remains elusive. In this study, we generated LKB1 knockout (KO) CRC cell lines by using CRISPR-Cas9. LKB1 KO promoted CRC cell motility in vitro and tumor metastases in vivo. LKB1 attenuated expression of TRAF2 and NCK-interacting protein kinase (TNIK) as accessed by RNA-seq and western blots, and similar suppression was also detected in the tumor tissues of azoxymethane/dextran sodium sulfate-induced intestinal-specific LKB1-KO mice. LKB1 repressed TNIK expression through its kinase activity. Moreover, attenuating TNIK by shRNA inhibited cell migration and invasion of CRC cells. LKB1 loss-induced high metastatic potential of CRC cells was depended on TNIK upregulation. Furthermore, TNIK interacted with ARHGAP29 and further affected actin cytoskeleton remodeling. Taken together, LKB1 deficiency promoted CRC cell metastasis via TNIK upregulation and subsequently mediated cytoskeleton remodeling. These results suggest that LKB1-TNIK axis may play a crucial role in CRC progression.
结直肠癌（CRC）是最常见的恶性肿瘤之一。约5%-6%的CRC病例与遗传性CRC综合征有关，包括黑斑息肉综合征（PJS）。肝脏激酶B1（LKB1），也称为STK11，是导致PJS的主要基因。LKB1杂合性缺陷与小鼠肠道息肉有关，而LKB1在CRC中的作用机制仍不清楚。在本研究中，我们使用CRISPR-Cas9技术构建了LKB1基因敲除（KO）的CRC细胞系。LKB1基因敲除促进了CRC细胞在体外的运动能力和在体内的肿瘤转移。通过RNA测序和蛋白质免疫印迹分析发现，LKB1减弱了肿瘤坏死因子受体相关因子2（TRAF2）和NCK相互作用蛋白激酶（TNIK）的表达，在氧化偶氮甲烷/葡聚糖硫酸钠诱导的肠道特异性LKB1基因敲除小鼠的肿瘤组织中也检测到了类似的抑制作用。LKB1通过其激酶活性抑制TNIK的表达。此外，通过短发夹RNA（shRNA）减弱TNIK的表达可抑制CRC细胞的迁移和侵袭。LKB1缺失诱导的CRC细胞高转移潜能依赖于TNIK的上调。此外，TNIK与ARHGAP29相互作用，进一步影响肌动蛋白细胞骨架重塑。综上所述，LKB1缺陷通过上调TNIK促进CRC细胞转移，随后介导细胞骨架重塑。这些结果表明，LKB1-TNIK轴可能在CRC进展中起关键作用。
