Long noncoding RNAs play an important role in the occurrence, invasion, as well as metastasis of various human cancers, including hepatocellular carcinoma. Long noncoding RNAs can affect the biological functions of hepatocellular carcinoma cells by regulating various genes; however, only a small fraction of molecular mechanisms of long noncoding RNAs have been elucidated. In the present study, lnc AC010973.1 (lnc-ATG9B-4) was first identified by microarray analysis from 8 patients with hepatocellular carcinoma and confirmed by quantitative PCR in 176 patients with hepatocellular carcinoma. We demonstrated that lnc-ATG9B-4 was tightly relative to the tumorous size, TNM stages, portal vein tumor thrombus (PVTT), the tumor capsule, metastasis, degree of differentiation, and poor prognosis of hepatocellular carcinoma according to long-term follow-up data. In hepatocellular carcinoma cells, overexpression of lnc-ATG9B-4 promoted proliferation, invasion, as well as migration, while inhibiting lnc-ATG9B-4 by siRNA significantly attenuated the proliferation, invasion, as well as migration. Interestingly, lnc-ATG9B-4 increased the expression of cyclin-dependent kinase 5 (CDK5), which was closely related to the development and chemotherapy sensitivity of hepatocellular carcinoma. In summary, our results revealed that lnc-ATG9B-4 suggests an unfavorable prognosis of hepatocellular carcinoma and facilitates the proliferation, invasion, as well as migration of hepatocellular carcinoma cells by upregulating CDK5. This research suggests that lnc-ATG9B-4 may be a new biomarker for predicting the prognosis of hepatocellular carcinoma; meanwhile, targeting lnc-ATG9B-4 might serve as a potential strategy for the treatment hepatocellular carcinoma.

Impact statement

In this study, we explored the expression profile of lncRNA in HCC tumor tissues and paracancerous tissues using microarray assays. Furthermore, a new lncRNA (lnc-ATG9B-4) was identified, which was about 3.5 times more expressed in tumor tissues than in paracancerous tissues. Through clinicopathological analysis, lnc-ATG9B-4 was determined to be related to the tumorous size, TNM stages, portal vein tumor thrombus (PVTT), the tumor capsule, metastasis, and the degree of differentiation. Lnc-ATG9B-4 promoted the proliferation, invasion, as well as migration of the HCC cells by upregulating the expression of CDK5. Here, we further exploited the molecular mechanisms of lnc-ATG9B-4 to screen new drug intervention targets for recurrence and metastasis of HCC.

中文翻译：

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Lnc-ATG9B-4通过上调CDK5通过细胞增殖和迁移加剧肝细胞癌的进展

长链非编码 RNA 在包括肝细胞癌在内的各种人类癌症的发生、侵袭和转移中发挥重要作用。长链非编码RNAs可以通过调控多种基因来影响肝癌细胞的生物学功能；然而，只有一小部分长链非编码 RNA 的分子机制被阐明。在本研究中，lnc AC010973.1 (lnc-ATG9B-4) 首先通过微阵列分析从 8 名肝细胞癌患者中鉴定出来，并通过定量 PCR 在 176 名肝细胞癌患者中得到证实。我们证明 lnc-ATG9B-4 与肿瘤大小、TNM 分期、门静脉癌栓 (PVTT)、肿瘤包膜、转移、分化程度、长期随访资料显示肝细胞癌预后不良。在肝细胞癌细胞中，lnc-ATG9B-4 的过表达促进增殖、侵袭和迁移，而通过 siRNA 抑制 lnc-ATG9B-4 显着减弱增殖、侵袭和迁移。有趣的是，lnc-ATG9B-4增加了细胞周期蛋白依赖性激酶5（CDK5）的表达，这与肝细胞癌的发展和化疗敏感性密切相关。总之，我们的结果表明 lnc-ATG9B-4 提示肝细胞癌的不良预后，并通过上调 CDK5 促进肝细胞癌细胞的增殖、侵袭和迁移。本研究提示lnc-ATG9B-4可能成为预测肝细胞癌预后的新生物标志物；同时，靶向 lnc-ATG9B-4 可能作为治疗肝细胞癌的潜在策略。

影响陈述

在本研究中，我们使用微阵列分析探索了 lncRNA 在 HCC 肿瘤组织和癌旁组织中的表达谱。此外，鉴定出一种新的 lncRNA (lnc-ATG9B-4)，其在肿瘤组织中的表达量是癌旁组织的 3.5 倍。通过临床病理分析，确定lnc-ATG9B-4与肿瘤大小、TNM分期、门静脉癌栓（PVTT）、肿瘤包膜、转移和分化程度有关。Lnc-ATG9B-4通过上调CDK5的表达促进HCC细胞的增殖、侵袭和迁移。在这里，我们进一步利用 lnc-ATG9B-4 的分子机制来筛选 HCC 复发和转移的新药物干预靶点。