Department of General Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China.
Department of Hepatobiliary Surgery, Affiliated Hospital, Guilin Medical University, Guilin, 541001, China.
Cell Death Dis. 2018 Jan 26;9(2):130. doi: 10.1038/s41419-017-0131-3.
The δ opioid receptor (DOR) is involved in the regulation of malignant transformation and tumor progression of hepatocellular carcinoma (HCC). However, regulation of the DOR in HCC remains poorly defined. We found that miR-874 was identified as a negative regulator of the DOR, which is a direct and functional target of miR-874 via its 3' untranslated region (UTR). Moreover, miR-874 was downregulated in HCC and its expression was inversely correlated with DOR expression. Downregulation of miR-874 was also associated with larger tumor size, more vascular invasion, a poor TNM stage, poor tumor differentiation, and inferior patient outcomes. Functionally, overexpression of miR-874 in the HCC cell line SK-hep-1 inhibited cell growth, migration, in vitro invasion, and in vivo tumorigenicity. Furthermore, miR-874 overexpression suppressed the DOR, resulting in a downregulated epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK) phosphorylation. The EGFR activator-epidermal growth factor (EGF)-can rescue the proliferation and migration suppression induced by miR-874 overexpression, and the rescue effects of the EGF were blocked by an ERK inhibitor. Our study results suggest that miRNA-874 is a negative regulator of the DOR that can suppress tumor proliferation and metastasis in HCC by targeting the DOR/EGFR/ERK pathway, which may be a potential target for HCC treatment.
δ 阿片受体（DOR）参与调控肝癌（HCC）的恶性转化和肿瘤进展。然而，DOR 在 HCC 中的调控作用仍未明确。我们发现，miR-874 是 DOR 的负调控因子，可通过其 3'非翻译区（UTR）直接靶向 miR-874 并发挥功能。此外，miR-874 在 HCC 中下调，其表达与 DOR 表达呈负相关。miR-874 的下调还与肿瘤体积较大、血管侵犯较多、TNM 分期较差、肿瘤分化较差和患者预后不良有关。功能上，在 HCC 细胞系 SK-hep-1 中过表达 miR-874 可抑制细胞生长、迁移、体外侵袭和体内致瘤性。此外，miR-874 的过表达抑制了 DOR，导致表皮生长因子受体（EGFR）和细胞外信号调节激酶（ERK）磷酸化下调。EGFR 激活剂-表皮生长因子（EGF）可挽救由 miR-874 过表达引起的增殖和迁移抑制，而 ERK 抑制剂可阻断 EGF 的挽救作用。我们的研究结果表明，miR-874 是 DOR 的负调控因子，可通过靶向 DOR/EGFR/ERK 通路抑制 HCC 中的肿瘤增殖和转移，这可能是 HCC 治疗的潜在靶点。
