Chen Yueda, Ye Botian, Wang Chunyan, Nie Yanyan, Qin Jing, Shen Zhenbin
Department of General Surgery, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, Fujian, 361015, China.
Department of General Surgery, Gastric Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Cell Death Discov. 2022 Jul 14;8(1):321. doi: 10.1038/s41420-022-01103-4.
Human epidermal growth factor receptor 2 (HER-2), a famous therapeutic target for breast cancer, is also associated with an increased risk of recurrence and poor outcomes of other malignancies, including gastric cancer. Yet the mechanism of HER-2 therapy resistance remains controversial due to the heterogeneity of gastric adenocarcinoma. We know, Procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 3 (PLOD3), a key gene coding enzymes that catalyze the lysyl hydroxylation of extracellular matrix collagen, plays an important contributor to HER-2 targeting agent Trastuzumab resistance in gastric cancer. Herein, we analyzed clinical samples of gastric cancer patients and gastric cancer cell lines and identified PLOD3, unveiled that depletion of PLOD3 leads to decreased cell proliferation, tumor growth and Trastuzumab sensitivity in these Trastuzumab resistant GC cell lines. Clinically, increased PLOD3 expression correlates with decreased Trastuzumab therapy responsiveness in GC patients. Mechanistically, we show that PLOD3 represses tumor suppressor FoxO3 expression, therefore upregulating Survivin protein expression that contributes to Trastuzumab resistance in GC. Therefore, our study identifies a new signaling axis PLOD3-FoxO3- Survivin pathway that may be therapeutically targeted in HER-2 positive gastric cancer.
人表皮生长因子受体2（HER-2）是乳腺癌著名的治疗靶点，也与包括胃癌在内的其他恶性肿瘤复发风险增加和预后不良有关。然而，由于胃腺癌的异质性，HER-2治疗耐药的机制仍存在争议。我们知道，原胶原赖氨酸2-氧代戊二酸5-双加氧酶3（PLOD3）是一种编码催化细胞外基质胶原赖氨酰羟化的酶的关键基因，在胃癌中是HER-2靶向药物曲妥珠单抗耐药的重要因素。在此，我们分析了胃癌患者的临床样本和胃癌细胞系，鉴定出PLOD3，发现PLOD3的缺失导致这些曲妥珠单抗耐药的胃癌细胞系中细胞增殖、肿瘤生长和曲妥珠单抗敏感性降低。临床上，PLOD3表达增加与胃癌患者曲妥珠单抗治疗反应性降低相关。从机制上讲，我们表明PLOD3抑制肿瘤抑制因子FoxO3的表达，从而上调Survivin蛋白表达，这有助于胃癌中的曲妥珠单抗耐药。因此，我们的研究确定了一个新的信号轴PLOD3-FoxO3-Survivin通路，该通路可能是HER-2阳性胃癌的治疗靶点。
