Institute of Biochemistry, Emil-Fischer-Zentrum.
Department of Medicine 1, University Hospital Erlangen, and.
J Clin Invest. 2020 May 1;130(5):2509-2526. doi: 10.1172/JCI131919.
Hepatocellular carcinoma (HCC) is clearly age-related and represents one of the deadliest cancer types worldwide. As a result of globally increasing risk factors including metabolic disorders, the incidence rates of HCC are still rising. However, the molecular hallmarks of HCC remain poorly understood. Neuropeptide Y (NPY) and NPY receptors represent a highly conserved, stress-activated system involved in diverse cancer-related hallmarks including aging and metabolic alterations, but its impact on liver cancer had been unclear. Here, we observed increased expression of NPY5 receptor (Y5R) in HCC, which correlated with tumor growth and survival. Furthermore, we found that its ligand NPY was secreted by peritumorous hepatocytes. Hepatocyte-derived NPY promoted HCC progression by Y5R activation. TGF-β1 was identified as a regulator of NPY in hepatocytes and induced Y5R in invasive cancer cells. Moreover, NPY conversion by dipeptidylpeptidase 4 (DPP4) augmented Y5R activation and function in liver cancer. The TGF-β/NPY/Y5R axis and DPP4 represent attractive therapeutic targets for controlling liver cancer progression.
肝细胞癌 (HCC) 与年龄明显相关，是全球最致命的癌症类型之一。由于代谢紊乱等全球风险因素的增加，HCC 的发病率仍在上升。然而，HCC 的分子特征仍知之甚少。神经肽 Y (NPY) 和 NPY 受体代表一个高度保守的、应激激活的系统，参与多种与癌症相关的特征，包括衰老和代谢改变，但它对肝癌的影响尚不清楚。在这里，我们观察到 HCC 中 NPY5 受体 (Y5R) 的表达增加，这与肿瘤生长和存活相关。此外，我们发现其配体 NPY 由肿瘤周围的肝细胞分泌。肝细胞衍生的 NPY 通过 Y5R 激活促进 HCC 进展。转化生长因子-β1 (TGF-β1) 被鉴定为肝细胞中 NPY 的调节剂，并诱导侵袭性癌细胞中 Y5R 的表达。此外，二肽基肽酶 4 (DPP4) 对 NPY 的转化增强了肝癌中 Y5R 的激活和功能。TGF-β/NPY/Y5R 轴和 DPP4 是控制肝癌进展的有吸引力的治疗靶点。
