miR-612 通过 HADHA 介导的脂质重编程调节肝癌侵袭伪足。
MiR-612 regulates invadopodia of hepatocellular carcinoma by HADHA-mediated lipid reprogramming.
机构信息
Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
出版信息
J Hematol Oncol. 2020 Feb 7;13(1):12. doi: 10.1186/s13045-019-0841-3.
BACKGROUND
MicroRNA-612 (miR-612) has been proven to suppress EMT, stemness, and tumor metastasis of hepatocellular carcinoma (HCC) via PI3K/AKT2 and Sp1/Nanog signaling. However, its biological roles on HCC progression are far from elucidated.
METHODS
We found direct downstream target of miR-612, hadha by RNA immunoprecipitation and sequencing. To explore its biological characteristic, potential molecular mechanism, and clinical relevance in HCC patients, we performed several in-vitro and in-vivo models, as well as human tissue chip.
RESULTS
Ectopic expression of miR-612 could partially reverse the level of HADHA, then suppress function of pseudopods, and diminish metastatic and invasive potential of HCC by lipid reprogramming. In detail, miR-612 might reduce invadopodia formation via HADHA-mediated cell membrane cholesterol alteration and accompanied with the inhibition of Wnt/β-catenin regulated EMT occurrence. Our results showed that the maximum oxygen consumption rates (OCR) of HCCLM3 and HCCLM3 cells were decreased nearly by 40% and 60% of their counterparts (p < 0.05). The levels of acetyl CoA were significantly decreased, about 1/3 (p > 0.05) or 1/2 (p < 0.05) of their controls, in exogenous miR-612 or hadha-shRNA transfected HCCLM3 cell lines. Besides, overexpression of hadha cell lines had a high expression level of total cholesterol, especially 27-hydroxycholesterol (p < 0.005). SREBP2 protein expression level as well as its downstream targets, HMGCS1, HMGCR, MVD, SQLE were all deregulated by HADHA. Meanwhile, the ATP levels were reduced to 1/2 and 1/4 in HCCLM3 (p < 0.05) and HCCLM3 (p < 0.01) respectively. Moreover, patients with low miR-612 levels and high HADHA levels had a poor prognosis with shorter overall survival.
CONCLUSION
miR-612 can suppress the formation of invadopodia, EMT, and HCC metastasis and by HADHA-mediated lipid programming, which may provide a new insight of miR-612 on tumor metastasis and progression.
背景
MicroRNA-612（miR-612）已被证明通过 PI3K/AKT2 和 Sp1/Nanog 信号通路抑制肝癌（HCC）的 EMT、干性和肿瘤转移。然而，其在 HCC 进展中的生物学作用仍远未阐明。
方法
我们通过 RNA 免疫沉淀和测序发现 miR-612 的直接下游靶标 HADHA。为了探讨其在 HCC 患者中的生物学特征、潜在分子机制和临床相关性，我们进行了多种体内外模型以及人类组织芯片实验。
结果
外源性表达 miR-612 可部分逆转 HADHA 水平，然后通过脂质重编程抑制 HCC 的伪足形成，降低其转移和侵袭潜能。具体而言，miR-612 可能通过 HADHA 介导的细胞膜胆固醇改变减少侵袭伪足的形成，并伴随着 Wnt/β-catenin 调控的 EMT 发生的抑制。我们的结果表明，HCCLM3 和 HCCLM3 细胞的最大耗氧量（OCR）分别降低了近 40%和 60%（p<0.05）。外源性 miR-612 或 hadha-shRNA 转染 HCCLM3 细胞系中乙酰辅酶 A 的水平显著降低，约为对照的 1/3（p>0.05）或 1/2（p<0.05）。此外，HADHA 过表达细胞系的总胆固醇，尤其是 27-羟胆固醇水平（p<0.005）升高。SREBP2 蛋白表达水平及其下游靶标 HMGCS1、HMGCR、MVD、SQLE 均被 HADHA 调控。同时，HCCLM3（p<0.05）和 HCCLM3（p<0.01）中的 ATP 水平分别降低至 1/2 和 1/4。此外，miR-612 水平低且 HADHA 水平高的患者总体生存率较差，预后不良。
结论
miR-612 可通过 HADHA 介导的脂质编程抑制侵袭伪足、EMT 和 HCC 转移的形成，这可能为 miR-612 对肿瘤转移和进展提供新的见解。
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