College of Pharmacy, Gannan Medical University, Ganzhou, Jiangxi, China.
Department of Gastroenterology, The First Affiliated Hospital, Gannan Medical University, Ganzhou, Jiangxi, China.
Cell Mol Life Sci. 2021 Dec;78(24):8261-8281. doi: 10.1007/s00018-021-04013-3. Epub 2021 Nov 13.
Colorectal cancer (CRC) is the leading cause of cancer-related mortality worldwide, which makes it urgent to identify novel therapeutic targets for CRC treatment. In this study, DHX9 was filtered out as the prominent proliferation promoters of CRC by siRNA screening. Moreover, DHX9 was overexpressed in CRC cell lines, clinical CRC tissues and colitis-associated colorectal cancer (CAC) mouse model. The upregulation of DHX9 was positively correlated with poor prognosis in patients with CRC. Through gain- and loss-of function experiments, we found that DHX9 promoted CRC cell proliferation, colony formation, apoptosis resistance, migration and invasion in vitro. Furthermore, a xenograft mouse model and a hepatic metastasis mouse model were utilized to confirm that forced overexpression of DHX9 enhanced CRC outgrowth and metastasis in vivo, while DHX9 ablation produced the opposite effect. Mechanistically, from one aspect, DHX9 enhances p65 phosphorylation, promotes p65 nuclear translocation to facilitate NF-κB-mediated transcriptional activity. From another aspect, DHX9 interacts with p65 and RNA polymerase II (RNA Pol II) to enhance the downstream targets of NF-κB (e.g., Survivin, Snail) expression to potentiate the malignant phenotypes of CRC. Together, our results suggest that DHX9 may be a potential therapeutic target for prevention and treatment of CRC patients.
结直肠癌（CRC）是全球癌症相关死亡的主要原因，因此迫切需要确定 CRC 治疗的新治疗靶点。在这项研究中，通过 siRNA 筛选，DHX9 被筛选为 CRC 的显著增殖促进因子。此外，DHX9 在 CRC 细胞系、临床 CRC 组织和结肠炎相关结直肠癌（CAC）小鼠模型中过表达。DHX9 的上调与 CRC 患者的预后不良呈正相关。通过增益和缺失功能实验，我们发现 DHX9 促进 CRC 细胞在体外的增殖、集落形成、抗凋亡、迁移和侵袭。此外，利用异种移植小鼠模型和肝转移小鼠模型证实，DHX9 的强制过表达增强了 CRC 在体内的生长和转移，而 DHX9 的缺失则产生了相反的效果。从一方面来看，DHX9 增强了 p65 的磷酸化，促进了 p65 向核内易位，从而促进 NF-κB 介导的转录活性。另一方面，DHX9 与 p65 和 RNA 聚合酶 II（RNA Pol II）相互作用，增强 NF-κB 的下游靶标（例如 Survivin、Snail）的表达，从而增强 CRC 的恶性表型。总之，我们的研究结果表明，DHX9 可能是预防和治疗 CRC 患者的潜在治疗靶点。
