Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
Cell Death Dis. 2022 May 14;13(5):463. doi: 10.1038/s41419-022-04859-w.
LHPP, a histidine phosphatase, has been implicated in tumour progression. However, its role, underlying mechanisms, and prognostic significance in human gastric cancer (GC) are elusive. Here, we obtained GC tissues and corresponding normal tissues from 48 patients and identified LHPP as a downregulated gene via RNA-seq. qRT-PCR and western blotting were applied to examine LHPP levels in normal and GC tissues. The prognostic value of LHPP was elucidated using tissue microarray and IHC analyses in two independent GC cohorts. The functional roles and mechanistic insights of LHPP in GC growth and metastasis were evaluated in vitro and in vivo. The results showed that LHPP expression was significantly decreased in GC tissues at both the mRNA and protein levels. Multivariate Cox regression analysis revealed that LHPP was an independent prognostic factor and effective predictor in patients with GC. The low expression of LHPP was significantly related to the poor prognosis and chemotherapy sensitivity of gastric cancer patients. Moreover, elevated LHPP expression effectively suppressed GC growth and metastasis in vitro and in vivo. Mechanistically, the m6A modification of LHPP mRNA by METTL14 represses its expression; LHPP inhibits the phosphorylation of GSK3b through acetylation and mediates HIF1A to inhibit glycolysis, proliferation, invasion and metastasis of gastric cancer cells. Together, our findings suggest that LHPP is regulated by m6A methylation and regulates the metabolism of GC by changing the acetylation level. Thus, LHPP is a potential predictive biomarker and therapeutic target for GC.
LHPP，一种组氨酸磷酸酶，与肿瘤进展有关。然而，其在人类胃癌（GC）中的作用、潜在机制和预后意义仍不清楚。在这里，我们从 48 名患者中获得了 GC 组织和相应的正常组织，并通过 RNA-seq 鉴定 LHPP 为下调基因。qRT-PCR 和 Western blot 用于检测正常和 GC 组织中的 LHPP 水平。通过组织微阵列和 IHC 分析在两个独立的 GC 队列中阐明了 LHPP 的预后价值。在体外和体内评估了 LHPP 在 GC 生长和转移中的功能作用和机制见解。结果表明，LHPP 在 GC 组织中的表达在 mRNA 和蛋白水平均显著降低。多变量 Cox 回归分析显示，LHPP 是 GC 患者的独立预后因素和有效预测因子。LHPP 的低表达与胃癌患者的不良预后和化疗敏感性显著相关。此外，LHPP 表达的升高可有效抑制 GC 的体外和体内生长和转移。机制上，METTL14 通过 m6A 修饰 LHPP mRNA 抑制其表达；LHPP 通过乙酰化抑制 GSK3b 的磷酸化，并介导 HIF1A 抑制胃癌细胞的糖酵解、增殖、侵袭和转移。总之，我们的研究结果表明，LHPP 受 m6A 甲基化调节，并通过改变乙酰化水平调节 GC 的代谢。因此，LHPP 是 GC 的潜在预测生物标志物和治疗靶点。
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