DHX9 contributes to the malignant phenotypes of colorectal cancer via activating NF-κB signaling pathway
DHX9 contributes to the malignant phenotypes of colorectal cancer via activating NF-κB signaling pathway
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DOI：
10.1007/s00018-021-04013-3
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发表时间：
2021-11-13
影响因子：
8
通讯作者：
Liu, Zhiping
中科院分区：
文献类型：
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作者：
Liu, Shenglan;He, Liangmei;Liu, Zhiping
结直肠癌（CRC）是世界范围内癌症相关死亡的主要原因，这使得迫切需要确定新的治疗CRC的治疗靶点。在本研究中，DHX 9通过siRNA筛选作为CRC的突出增殖促进剂而被过滤掉。此外，DHX 9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。DHX 9的上调与CRC患者的不良预后正相关。通过功能获得和丧失实验，我们发现DHX 9在体外促进CRC细胞增殖、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来证实DHX 9的强制过表达增强体内CRC生长和转移，而DHX 9消融产生相反的效果。从机制上讲，一方面，DHX 9增强p65磷酸化，促进p65核转位以促进NF-κ B介导的转录活性。另一方面，DHX 9与p65和RNA聚合酶II（RNA Pol II）相互作用以增强NF-κ B的下游靶标（例如，Survivin、Snail）表达增强CRC的恶性表型。总之，我们的结果表明DHX 9可能是预防和治疗CRC患者的潜在治疗靶点。
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-kappa B-mediated transcriptional activity. From another aspect, DHX9 interacts with p65 and RNA polymerase II (RNA Pol II) to enhance the downstream targets of NF-kappa B (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.