State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China.
Cancer Res. 2021 Mar 1;81(5):1361-1374. doi: 10.1158/0008-5472.CAN-20-2480. Epub 2020 Dec 23.
AKR1C3 is an enzyme belonging to the aldo-ketoreductase family, the members of which catalyze redox transformations involved in biosynthesis, intermediary metabolism, and detoxification. AKR1C3 plays an important role in tumor progression and metastasis, however, little is known about the function and the molecular mechanism underlying the role of AKR1C3 in hepatocellular carcinoma (HCC). In this study, we report that AKR1C3 is significantly upregulated in HCC and that increased AKR1C3 is associated with poor survival. AKR1C3 positively regulated HCC cell proliferation and metastasis and . AKR1C3 promoted tumor proliferation and metastasis by activating NF-κB signaling. Furthermore, AKR1C3 regulated NF-κB activity by modulating TRAF6 and inducing its autoubiquitination in HCC cells. Activation of NF-κB released proinflammatory factors that facilitated the phosphorylation of STAT3 and increased tumor cell proliferation and invasion. Gain- and loss-of-function experiments showed that AKR1C3 promoted tumor proliferation and invasion via the IL6/STAT3 pathway. STAT3 also directly bound the AKR1C3 promoter and increased transcription of AKR1C3, thereby establishing a positive regulatory feedback loop. Treatment with the AKR1C3 inhibitors indocin and medroxyprogesterone acetate inhibited tumor growth and invasion and promoted apoptosis in HCC cells. Collectively, these results indicate that a AKR1C3/NF-κB/STAT3 signaling loop results in HCC cell proliferation and metastasis and could be a promising therapeutic target in HCC. SIGNIFICANCE: These findings elucidate a novel AKR1C3-driven signaling loop that regulates proliferation and metastasis in HCC, providing potential prognostic and therapeutic targets in this disease.
AKR1C3 是醛酮还原酶家族的一种酶，该家族成员催化涉及生物合成、中间代谢和解毒的氧化还原转化。AKR1C3 在肿瘤进展和转移中发挥重要作用，然而，对于 AKR1C3 在肝细胞癌 (HCC) 中的作用的功能和分子机制知之甚少。在这项研究中，我们报告 AKR1C3 在 HCC 中显著上调，并且 AKR1C3 的增加与不良预后相关。AKR1C3 正向调节 HCC 细胞的增殖和转移。AKR1C3 通过激活 NF-κB 信号通路促进肿瘤增殖和转移。此外，AKR1C3 通过调节 TRAF6 并在 HCC 细胞中诱导其自泛素化来调节 NF-κB 活性。NF-κB 的激活释放了促炎因子，促进了 STAT3 的磷酸化，并增加了肿瘤细胞的增殖和侵袭。增益和缺失功能实验表明，AKR1C3 通过 IL6/STAT3 通路促进肿瘤增殖和侵袭。STAT3 还直接结合 AKR1C3 启动子并增加 AKR1C3 的转录，从而建立了正反馈调节回路。AKR1C3 抑制剂吲哚美辛和醋酸甲地孕酮的治疗抑制了 HCC 细胞的生长和侵袭，并促进了细胞凋亡。总之，这些结果表明 AKR1C3/NF-κB/STAT3 信号通路导致 HCC 细胞增殖和转移，可能成为 HCC 的有前途的治疗靶点。
这些发现阐明了一个新的 AKR1C3 驱动的信号环路，调节 HCC 中的增殖和转移，为该疾病提供了潜在的预后和治疗靶点。
