LHPP inhibits cell growth and migration and triggers autophagy in papillary thyroid cancer by regulating the AKT/AMPK/mTOR signaling pathway
LHPP inhibits cell growth and migration and triggers autophagy in papillary thyroid cancer by regulating the AKT/AMPK/mTOR signaling pathway
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DOI：
10.1093/abbs/gmaa015
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发表时间：
2020-04-01
影响因子：
3.7
通讯作者：
Wang, Zhuoying
中科院分区：
文献类型：
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作者：
Sun, Wenyu;Qian, Kai;Wang, Zhuoying
近几十年来，甲状腺乳头状癌（PTC）的发病率迅速上升。然而，PTC生理和病理过程的分子机制仍不清楚。磷酸赖氨酸磷酸组氨酸无机焦磷酸磷酸酶（LHPP）是一种肿瘤抑制因子，在多种人类癌症中发挥抗肿瘤作用，但LHPP在PTC中的作用及其机制尚不清楚。在本研究中，我们首先评估LHPP在PTC中的作用，并探讨其潜在的机制。采用临床标本检测PTC组织及癌旁正常组织中LHPP的表达。LHPP在PTC组织中的表达低于癌旁正常组织。LHPP在PTC细胞系中的表达模式与正常人甲状腺滤泡上皮细胞相似。然后，我们在三种PTC细胞系中过表达LHPP，结果表明异位LHPP表达一贯地降低细胞活力、增殖和迁移，并触发细胞自噬。此外，LHPP的过表达抑制了AKT/mTOR信号通路的激活，促进了AMPK信号通路的激活。此外，AKT/mTOR信号通路的激活和AMPK信号通路的抑制恢复了LHPP在PTC细胞系中异位表达的作用，表明LHPP通过调节AKT/AMPK/mTOR信号通路发挥其抗肿瘤活性。最后，我们阐明了异位LHPP表达抑制体内PTC肿瘤生长。结论：LHPP在PTC中具有抗肿瘤作用，提示LHPP可能是PTC诊断和治疗的有效靶点。
In recent decades, the incidence rate of papillary thyroid carcinoma (PTC) has been rapidly increasing. However, the molecular mechanism of the physiological and pathological processes of PTC is still largely unknown. Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) is a tumor suppressor and exerts anti-tumor effect in several human cancers, while the role and underlying mechanism of LHPP in PTC remain vague. In this study, we firstly evaluated the roles of LHPP in PTC and explored its underlying mechanism. Using clinical tissue samples, we detected the level of LHPP in PTC tissues and in matched adjacent normal tissues. Lower level of LHPP was found in PTC tissues than in matched adjacent normal tissues. Similar LHPP expression pattern was found in PTC cell lines when compared with that in normal human thyroid follicular epithelial cells. Then, we over-expressed LHPP in three PTC cell lines and results showed that ectopic LHPP expression consistently reduced cell viability, proliferation, and migration and triggered cell autophagy. Furthermore, over-expression of LHPP inhibited the activation of the AKT/mTOR pathway and promoted the AMPK signaling pathway. In addition, the activation of AKT/mTOR and inhibition of AMPK signaling pathways restored the role of ectopic LHPP expression in PTC cell lines, indicating that LHPP exerts its anti-tumor activity through regulating the AKT/AMPK/mTOR pathway. Ultimately, we illustrated that ectopic LHPP expression inhibited PTC tumor growth in vivo. In conclusion, we revealed that LHPP has an anti-tumor effect in PTC and indicated that LHPP might serve as an effective diagnostic and therapeutic target for PTC.