Guangzhou University of Chinese Medicine, Guangzhou, 510405, Guangdong, China.
Integrative Cancer Centre, the First Affiliated Hospital of Guangzhou, University of Chinese Medicine, Guangzhou, China.
BMC Complement Altern Med. 2019 Nov 19;19(1):318. doi: 10.1186/s12906-019-2718-y.
Altered cellular metabolism is considered to be one of the hallmarks of cancer (Coller, Am J Pathol 184:4-17, 2014; Kim and Bae, Curr Opin Hematol 25:52-59, 2018). However, few studies have investigated the role of metabolism in the development of gastric precancerous lesions (GPLs). Weipiling (WPL), a traditional Chinese medicine formula for treatment of GPLs. In this study, we evaluated the amelioration of GPLs by WPL and investigated the possible role of WPL in regulating glucose metabolism.
Firstly, the major components of WPL are chemically characterized by HPLC analytical method. In this study, we chose the Atp4a mouse model (Spicer etal., J Biol Chem 275:21555-21565, 2000) for GPL analysis. Different doses of WPL were administered orally to mice for 10 weeks. Next, the pathological changes of gastric mucosa were assessed by the H&E staining and AB-PAS staining. In addition, TUNEL staining was used to evaluate apoptosis, and we further used immunohistochemically labelled CDX2, MUC2, ki-67, PTEN, and p53 proteins to assess the characteristic changes of gastric mucosa in precancerous lesions. The levels of such transporters as HK-II, PKM2, ENO1, MPC1, and LDHA were determined by Western blot analysis. Finally, we assessed the expression of mTOR, HIF-1α, AMPK, Rheb, TSC1 and TSC2 protein in the gastric mucosa of Atp4amice.
In this work, we evaluated the protective effect of WPL on gastric mucosa in mice with precancerous lesions. The aberrant apoptosis in gastric mucosa of gastric pre-cancerous lesions was controlled by WPL (P<0.05). Furthermore, WPL suppressed the expression of CDX2, MUC2, ki-67, PTEN and p53, as the levels of these proteins decreased significantly compared with the model group (P<0.05). In parallel, WPL significantly suppressed the expression of transporters, such as HK-II, PKM2, ENO1, MPC1 and LDHA (P<0.05). In addition, mTOR, HIF-1a, AMPK, Rheb, TSC1 and TSC2 protein levels in gastric mucosa of Atp4a mice in the high- and low-dose WPL groups were significantly lower than those in the model group (P<0.05), while the expression of TSC1 and TSC2 protein was significantly higher (P<0.05).
Conclusively, WPL could ameliorate GPLs in Atp4a mice by inhibiting the expression of transporters and suppressing the aberrant activation of mTOR/HIF-1α.
细胞代谢改变被认为是癌症的标志之一（Coller，Am J Pathol 184:4-17, 2014；Kim 和 Bae，Curr Opin Hematol 25:52-59, 2018）。然而，很少有研究探讨代谢在胃癌前病变（GPL）发展中的作用。胃痞灵（WPL）是一种治疗 GPL 的中药方剂。在这项研究中，我们评估了 WPL 对 GPL 的改善作用，并探讨了 WPL 调节葡萄糖代谢的可能作用。
首先，采用高效液相色谱分析方法对 WPL 的主要成分进行化学表征。在本研究中，我们选择 Atp4a 小鼠模型（Spicer 等人，J Biol Chem 275:21555-21565, 2000）进行 GPL 分析。不同剂量的 WPL 通过口服给予小鼠 10 周。接下来，通过 H&E 染色和 AB-PAS 染色评估胃黏膜的病理变化。此外，通过 TUNEL 染色评估细胞凋亡，并用免疫组织化学标记的 CDX2、MUC2、ki-67、PTEN 和 p53 蛋白评估胃癌前病变胃黏膜的特征变化。Western blot 分析测定 HK-II、PKM2、ENO1、MPC1 和 LDHA 等转运体的水平。最后，我们评估了 Atp4a 小鼠胃黏膜中 mTOR、HIF-1α、AMPK、Rheb、TSC1 和 TSC2 蛋白的表达。
在这项工作中，我们评估了 WPL 对患有前病变的小鼠胃黏膜的保护作用。WPL 控制了胃黏膜前癌变中异常的细胞凋亡（P<0.05）。此外，WPL 抑制了 CDX2、MUC2、ki-67、PTEN 和 p53 的表达，与模型组相比，这些蛋白的水平显著降低（P<0.05）。同时，WPL 显著抑制了 HK-II、PKM2、ENO1、MPC1 和 LDHA 等转运体的表达（P<0.05）。此外，高、低剂量 WPL 组 Atp4a 小鼠胃黏膜中 mTOR、HIF-1a、AMPK、Rheb、TSC1 和 TSC2 蛋白水平明显低于模型组（P<0.05），而 TSC1 和 TSC2 蛋白表达明显升高（P<0.05）。
综上所述，WPL 通过抑制转运体的表达和抑制 mTOR/HIF-1α 的异常激活，可改善 Atp4a 小鼠的 GPL。
