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Abstract：
BACKGROUND: Neoadjuvant chemotherapy (NACT) is routinely used to treat patients with advanced gastric cancer (AGC). However, the identification of reliable markers to determine which AGC patients would benefit from NACT remains challenging.
METHODS: A systematic screening of plasma proteins between NACT-sensitive and NACT-resistant AGC patients was performed by a mass spectrometer (n = 6). The effect of the most differential plasma protein was validated in two independent cohorts with AGC patients undergoing NACT (ELISA cohort: n = 155; Validated cohort: n = 203). The expression of this candidate was examined in a cohort of AGC tissues using immunohistochemistry (n = 34). The mechanism of this candidate on 5-Fluorouracil (5-FU) resistance was explored by cell-biology experiments in vitro and vivo.
RESULTS: A series of differential plasma proteins between NACT-sensitive and NACT-resistant AGC patients was identified. Among them, plasma HIST1H2BK was validated as a significant biomarker for predicting NACT response and prognosis. Moreover, HIST1H2BK was over-expression in NACT-resistant tissues compared to NACT-sensitive tissues in AGC. Mechanistically, HIST1H2BK inhibited 5-FU-induced apoptosis by upregulating A2M transcription and then activating LRP/PI3K/Akt pathway, thereby promoting 5-FU resistance in GC cells. Intriguingly, HIST1H2BK-overexpressing 5-FU-resistant GC cells propagated resistance to 5-FU-sensitive GC cells through the secretion of HIST1H2BK.
CONCLUSIONS: This study highlights significant differences in plasma protein profiles between NACT-resistant and NACT-sensitive AGC patients. Plasma HIST1H2BK emerged as an effective biomarker for achieving more accurate NACT in AGC. The mechanism of intracellular and secreted HIST1H2BK on 5-FU resistance provided a novel insight into chemoresistance in AGC.
METHODS: A systematic screening of plasma proteins between NACT-sensitive and NACT-resistant AGC patients was performed by a mass spectrometer (n = 6). The effect of the most differential plasma protein was validated in two independent cohorts with AGC patients undergoing NACT (ELISA cohort: n = 155; Validated cohort: n = 203). The expression of this candidate was examined in a cohort of AGC tissues using immunohistochemistry (n = 34). The mechanism of this candidate on 5-Fluorouracil (5-FU) resistance was explored by cell-biology experiments in vitro and vivo.
RESULTS: A series of differential plasma proteins between NACT-sensitive and NACT-resistant AGC patients was identified. Among them, plasma HIST1H2BK was validated as a significant biomarker for predicting NACT response and prognosis. Moreover, HIST1H2BK was over-expression in NACT-resistant tissues compared to NACT-sensitive tissues in AGC. Mechanistically, HIST1H2BK inhibited 5-FU-induced apoptosis by upregulating A2M transcription and then activating LRP/PI3K/Akt pathway, thereby promoting 5-FU resistance in GC cells. Intriguingly, HIST1H2BK-overexpressing 5-FU-resistant GC cells propagated resistance to 5-FU-sensitive GC cells through the secretion of HIST1H2BK.
CONCLUSIONS: This study highlights significant differences in plasma protein profiles between NACT-resistant and NACT-sensitive AGC patients. Plasma HIST1H2BK emerged as an effective biomarker for achieving more accurate NACT in AGC. The mechanism of intracellular and secreted HIST1H2BK on 5-FU resistance provided a novel insight into chemoresistance in AGC.
摘要：
背景：新辅助化疗（NACT）常规用于治疗晚期胃癌（AGC）患者。然而,确定哪些AGC患者将从NACT获益的可靠标志物仍然具有挑战性.
方法：通过质谱仪对NACT敏感和NACT抵抗的AGC患者之间的血浆蛋白进行系统筛选（n=6）。在经历NACT的AGC患者的两个独立队列中验证了差异最大的血浆蛋白的效果(ELISA队列:n=155;验证队列:n=203)。使用免疫组织化学(n=34)在一组AGC组织中检查该候选者的表达。通过体外和体内细胞生物学实验探索了该候选物对5-氟尿嘧啶（5-FU）抗性的机制。
结果：确定了NACT敏感和NACT抵抗AGC患者之间的一系列差异血浆蛋白。其中,血浆HIST1H2BK被验证为预测NACT反应和预后的重要生物标志物。此外，与AGC中的NACT敏感组织相比，HIST1H2BK在NACT抗性组织中过表达。机械上,HIST1H2BK通过上调A2M转录然后激活LRP/PI3K/Akt通路抑制5-FU诱导的细胞凋亡,从而促进GC细胞的5-FU抗性。有趣的是，过表达HIST1H2BK的5-FU抗性GC细胞通过分泌HIST1H2BK对5-FU敏感性GC细胞产生抗性。
结论：这项研究强调了NACT耐药和NACT敏感的AGC患者之间血浆蛋白谱的显著差异。血浆HIST1H2BK作为在AGC中实现更准确NACT的有效生物标志物出现。细胞内和分泌的HIST1H2BK对5-FU抗性的机制提供了对AGC化学抗性的新见解。
方法：通过质谱仪对NACT敏感和NACT抵抗的AGC患者之间的血浆蛋白进行系统筛选（n=6）。在经历NACT的AGC患者的两个独立队列中验证了差异最大的血浆蛋白的效果(ELISA队列:n=155;验证队列:n=203)。使用免疫组织化学(n=34)在一组AGC组织中检查该候选者的表达。通过体外和体内细胞生物学实验探索了该候选物对5-氟尿嘧啶（5-FU）抗性的机制。
结果：确定了NACT敏感和NACT抵抗AGC患者之间的一系列差异血浆蛋白。其中,血浆HIST1H2BK被验证为预测NACT反应和预后的重要生物标志物。此外，与AGC中的NACT敏感组织相比，HIST1H2BK在NACT抗性组织中过表达。机械上,HIST1H2BK通过上调A2M转录然后激活LRP/PI3K/Akt通路抑制5-FU诱导的细胞凋亡,从而促进GC细胞的5-FU抗性。有趣的是，过表达HIST1H2BK的5-FU抗性GC细胞通过分泌HIST1H2BK对5-FU敏感性GC细胞产生抗性。
结论：这项研究强调了NACT耐药和NACT敏感的AGC患者之间血浆蛋白谱的显著差异。血浆HIST1H2BK作为在AGC中实现更准确NACT的有效生物标志物出现。细胞内和分泌的HIST1H2BK对5-FU抗性的机制提供了对AGC化学抗性的新见解。
