Chiba Naokazu, Sunamura Makoto, Nakagawa Masashi, Koganezawa Itsuki, Yokozuka Kei, Kobayashi Toshimichi, Hikita Kosuke, Ozawa Yosuke, Okihara Masaaki, Sano Toru, Tomita Koichi, Tsutsui Rina, Sugimoto Masahiro, Kawachi Shigeyuki
Department of Digestive and Transplantation Surgery, Tokyo Medical University Hachioji Medical Center Tokyo, Japan.
Research and Development Center for Minimally Invasive Therapies Health Promotion and Preemptive Medicine, Tokyo Medical University Tokyo, Japan.
Am J Cancer Res. 2020 Aug 1;10(8):2570-2581. eCollection 2020.
For pancreatic cancer, the probability of distant metastasis can help choose the best course of treatment. The aim of this study is to establish the efficacy of hydroxyproline as a biomarker for distant metastasis for pancreatic cancer and to clarify the mechanism of EGLN/HIF1A axis that controls the invasion and metastasis. Metabolites (hydroxyproline) and genes (EGLN2 and EGLN3) were identified by metabolome analysis of the serum with pancreatic cancers with and without distant metastasis. The mechanism of EGLN/HIF1A axis including angiogenesis was examined in pancreatic cancer cells. Hydroxyproline associated with these mechanisms was evaluated to suggest the association with overall survival in pancreatic cancer. Decreased expression of EGLN2 and EGLN3 in pancreatic cancer, via the HIF1A and TGF ß1 pathway, was associated with the induction of angiogenic factors, increased vascular invasion, and poor overall patient survival. Hydroxyproline concentrations were regulated via the HIF1A pathway by EGLN2 and EGLN3, and that increased concentrations of hydroxyproline promote the invasion and metastasis of pancreatic cancer cells. These results suggested that the expression of hydroxyproline through the HIF1A pathway induced by EGLN2 and EGLN3 could be a surrogate marker for treatment and might predict distant metastasis in pancreatic cancer.
对于胰腺癌而言，远处转移的可能性有助于选择最佳治疗方案。本研究的目的是确定羟脯氨酸作为胰腺癌远处转移生物标志物的有效性，并阐明EGLN/HIF1A轴控制侵袭和转移的机制。通过对有或无远处转移的胰腺癌患者血清进行代谢组分析，鉴定代谢物（羟脯氨酸）和基因（EGLN2和EGLN3）。在胰腺癌细胞中研究了包括血管生成在内的EGLN/HIF1A轴机制。评估与这些机制相关的羟脯氨酸，以提示其与胰腺癌总生存期的关联。胰腺癌中EGLN2和EGLN3表达降低，通过HIF1A和TGFβ1途径，与血管生成因子的诱导、血管侵袭增加以及患者总体生存期差有关。羟脯氨酸浓度由EGLN2和EGLN3通过HIF1A途径调节，且羟脯氨酸浓度升高促进胰腺癌细胞的侵袭和转移。这些结果表明，由EGLN2和EGLN3通过HIF1A途径诱导的羟脯氨酸表达可能是治疗的替代标志物，并可能预测胰腺癌的远处转移。
