Department of Genetics, Zhejiang Provincial Key Laboratory of Genetic and Developmental Disorders, Institute of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P.R. China.
Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China.
Int J Oncol. 2020 Dec;57(6):1368-1380. doi: 10.3892/ijo.2020.5143. Epub 2020 Nov 2.
Hepatocellular carcinoma (HCC) is an invasive malignant neoplasm with a poor prognosis. The development of chemoresistance severely obstructs the chemotherapeutic efficiency of HCC treatment. Therefore, understanding the mechanisms of chemoresistance is important for improving the outcomes of patients with HCC. Eukaryotic translation initiation factor 5A2 (eIF5A2), which is considered to be an oncogene, has been reported to mediate chemoresistance in various types of cancer; however, its precise role in HCC remains unclear. Accumulating evidence has suggested that autophagy serves a dual role in cancer chemotherapy. The present study aimed to investigate the role of autophagy in eIF5A2‑mediated doxorubicin resistance in HCC. High expression levels of eIF5A2 in human HCC tissues were observed by immunohistochemistry using a tissue microarray, which was consistent with the results of reverse transcription‑quantitative PCR analysis in paired HCC and adjacent healthy tissues. HCC patient‑derived tumor xenograft mouse model was used for the in vivo study, and knockdown of eIF5A2 effectively enhanced the efficacy of doxorubicin chemotherapy compared with that in the control group. Notably, eIF5A2 served as a repressor in regulating autophagy under chemotherapy. Silencing of eIF5A2 induced doxorubicin sensitivity in HCC cells by triggering lethal autophagy. In addition, 5‑ethynyl‑2'‑deoxyuridine, lactate dehydrogenase release assay and calcein‑AM/PI staining were used to determine the enhanced autophagic cell death induced by the silencing of eIF5A2 under doxorubicin treatment. Suppression of autophagy attenuated the sensitivity of HCC cells to doxorubicin induced by eIF5A2 silencing. The results also demonstrated that knockdown of the Beclin 1 gene, which is an autophagy regulator, reversed the enhanced autophagic cell death and doxorubicin sensitivity induced by eIF5A2 silencing. Taken together, these results suggested eIF5A2 may mediate the chemoresistance of HCC cells by suppressing autophagic cell death under chemotherapy through a Beclin 1‑dependent pathway, and that eIF5A2 may be a novel potential therapeutic target for HCC treatment.
肝细胞癌（HCC）是一种预后不良的侵袭性恶性肿瘤。化学耐药性的发展严重阻碍了 HCC 治疗的化疗效率。因此，了解耐药机制对于改善 HCC 患者的预后非常重要。真核翻译起始因子 5A2（eIF5A2）被认为是一种癌基因，已被报道在各种类型的癌症中介导耐药性；然而，其在 HCC 中的确切作用尚不清楚。越来越多的证据表明，自噬在癌症化疗中具有双重作用。本研究旨在探讨自噬在 eIF5A2 介导的 HCC 多柔比星耐药中的作用。通过组织微阵列免疫组织化学观察到 eIF5A2 在人 HCC 组织中的高表达水平，这与配对 HCC 和相邻健康组织中逆转录-定量 PCR 分析的结果一致。使用 HCC 患者来源的肿瘤异种移植小鼠模型进行体内研究，与对照组相比，eIF5A2 的敲低有效增强了多柔比星化疗的疗效。值得注意的是，eIF5A2 在化疗下作为调节自噬的抑制剂。沉默 eIF5A2 通过触发致命自噬诱导 HCC 细胞对多柔比星敏感。此外，使用 5-乙炔基-2'-脱氧尿苷、乳酸脱氢酶释放测定和 calcein-AM/PI 染色来确定 eIF5A2 沉默在多柔比星处理下诱导的增强的自噬细胞死亡。自噬的抑制减弱了 eIF5A2 沉默诱导的 HCC 细胞对多柔比星的敏感性。结果还表明，Beclin 1 基因（一种自噬调节剂）的敲低逆转了 eIF5A2 沉默诱导的增强的自噬细胞死亡和多柔比星敏感性。综上所述，这些结果表明，eIF5A2 可能通过 Beclin 1 依赖途径抑制化疗下的自噬细胞死亡来介导 HCC 细胞的耐药性，并且 eIF5A2 可能是 HCC 治疗的一种新的潜在治疗靶点。
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