Nankai Hospital, Tianjin Medical University, Tianjin, China.
Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine for Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin, China.
Cancer Sci. 2023 Mar;114(3):908-920. doi: 10.1111/cas.15635. Epub 2022 Nov 17.
Whether proline deficiency is a metabolic vulnerability in colorectal tumors is unknown. The aim of this study was to investigate the effects of proline metabolism-related genes and exogenous proline on the progression of colorectal cancer (CRC). We aimed to further clarify the role of pyrroline-5-carboxylate reductase (PYCR) 2, a key enzyme of proline synthesis, in the regulation of colorectal intraperitoneal metastatic tumors. This study was carried out based on The Cancer Genome Atlas (TCGA) data, database analysis, single-cell functional analysis, tissue microarray, cell experiments, and animal models. We found that, PYCR2 mRNA and protein levels were upregulated in CRC. The mRNA level of PYCR2 was closely related to the prognosis and tumor metastasis of CRC patients. The upregulated PYCR2 expression was at least partly due to low promoter methylation levels. The nomogram constructed based on PYCR2 expression and clinical characteristics of CRC showed good accuracy in predicting lymph node metastasis. Pycr2 knockdown inhibited epithelial-mesenchymal transition (EMT) of mouse CRC cells. Proline supplementation did not rescue the inhibition of mouse CRC cell proliferation and migration by Pycr2 knockdown. Proline supplementation also did not rescue the suppression of subcutaneous tumors and intraperitoneal metastatic tumors in mice by Pycr2 knockdown. PYCR2 co-expressed genes in TCGA-CRC were enriched in epigenetic modification-related biological processes and molecular functions. Four small molecules with the lowest binding energy to the PYCR2 protein were identified. Collectively, Pycr2 knockdown inhibited mouse CRC progression in a proline-independent approach. PYCR2 may be a promising tumor metastasis predictor and therapeutic target in CRC.
脯氨酸缺乏是否是结直肠肿瘤的代谢脆弱性尚不清楚。本研究旨在探讨脯氨酸代谢相关基因和外源性脯氨酸对结直肠癌（CRC）进展的影响。我们旨在进一步阐明脯氨酸合成关键酶吡咯啉-5-羧酸还原酶（PYCR）2在调节结直肠腹膜内转移瘤中的作用。本研究基于癌症基因组图谱（TCGA）数据、数据库分析、单细胞功能分析、组织微阵列、细胞实验和动物模型进行。我们发现，CRC 中 PYCR2 mRNA 和蛋白水平上调。PYCR2 mRNA 水平与 CRC 患者的预后和肿瘤转移密切相关。PYCR2 表达上调至少部分归因于启动子低甲基化水平。基于 PYCR2 表达和 CRC 临床特征构建的列线图在预测淋巴结转移方面具有良好的准确性。Pycr2 敲低抑制了小鼠 CRC 细胞的上皮-间充质转化（EMT）。脯氨酸补充未能挽救 Pycr2 敲低对小鼠 CRC 细胞增殖和迁移的抑制作用。脯氨酸补充也未能挽救 Pycr2 敲低对小鼠皮下肿瘤和腹膜内转移瘤的抑制作用。TCGA-CRC 中与 PYCR2 共表达的基因富集在与表观遗传修饰相关的生物学过程和分子功能中。鉴定出与 PYCR2 蛋白结合能最低的四种小分子。总之，Pycr2 敲低以不依赖脯氨酸的方式抑制了小鼠 CRC 的进展。PYCR2 可能是 CRC 中一种有前途的肿瘤转移预测因子和治疗靶点。
