He Ling, Wu Ming-Zhe, Wang Xu-Bo, Qiu Xue-Shan, Wang En-Hua, Wu Guang-Ping
Department of Pathology, The First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang 110001, China.
Department of Gynecology, The First Hospital of China Medical University, Shenyang 110001, China.
J Cancer. 2019 Jun 9;10(16):3632-3638. doi: 10.7150/jca.33237. eCollection 2019.
Liver kinase B1 (LKB1) is a critical tumor suppressor that is frequently mutated in human cancers. LKB1 has serine/threonine protein kinase activity, which regulates gene expression by phosphorylation of Yes-Associated protein (YAP). The phosphorylation-dependent YAP shuttling is critically important intracellular mechanism in the Hippo pathway. In our previous study, we found that the amplification of hTERC was significant higher in the bronchial brushing cells of patients with lung cancer, however, the underlying molecular mechanism is not clear. In this study, we showed that LKB1 overexpression could phosphorylate YAP and promoted its nuclear rejection. Silencing LKB1 could dephosphorylate YAP and promoted its entry into the nucleus. Here, we found that LKB1 inhibited the mRNA expression and the amplification of hTERC. YAP further up-regulated hTERC at mRNA and gene amplification levels. Therefore, we suggest that LKB1 may inhibit the expression and amplification of hTERC through the axis of LKB1-pYAP(YAP)-hTERC.
肝脏激酶B1（LKB1）是一种关键的肿瘤抑制因子，在人类癌症中经常发生突变。LKB1具有丝氨酸/苏氨酸蛋白激酶活性，通过磷酸化Yes相关蛋白（YAP）来调节基因表达。磷酸化依赖性YAP穿梭是Hippo信号通路中至关重要的细胞内机制。在我们之前的研究中，我们发现肺癌患者支气管刷检细胞中hTERC的扩增显著更高，然而，其潜在的分子机制尚不清楚。在本研究中，我们表明LKB1过表达可使YAP磷酸化并促进其核排斥。沉默LKB1可使YAP去磷酸化并促进其进入细胞核。在此，我们发现LKB1抑制hTERC的mRNA表达和扩增。YAP在mRNA和基因扩增水平上进一步上调hTERC。因此，我们认为LKB1可能通过LKB1-pYAP（YAP）-hTERC轴抑制hTERC的表达和扩增。
