Institute of Biomedical and Allied Health Sciences, University of Health Sciences, Lahore, Pakistan.
Toxicology and Chemotherapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
J Cancer Res Clin Oncol. 2023 Jul;149(8):4825-4837. doi: 10.1007/s00432-022-04410-6. Epub 2022 Oct 17.
Ectopic expression of anticancer genes (ACGs) imposes antineoplastic effects on transformed cells. Clinically, reduced expression of these genes has been linked with poor prognosis, metastasis and chemo/radiotherapy resistance in cancers. Identifying expression pattern of ACGs is crucial to establish their prognostic and therapeutic relevance in colorectal cancer (CRC). In addition to the clinical perspective, naturally occurring compounds can be explored in parallel for inducing ACGs to achieve cancer cell-specific death.
Expression profiles of three ACGs (NOXA, PAR-4, TRAIL) were identified via real-time PCR in CRC clinical isolates. Time lapse-based expression modifications in ACGs were studied in a CRC liver metastasis animal model using microarray methodology. Effects of a purified plant protein (riproximin) on selected ACGs were identified in three primary and metastatic CRC cell lines by real-time PCR. Lastly, importance of the ACGs in a cellular environment was highlighted via bioinformatic analysis.
ACGs (except NOXA) were persistently downregulated in clinical isolates when comparing the overall mean expression values with normal mucosa levels. In vivo studies showed a prominent inhibition of NOXA and PAR-4 genes in implanted CRC cells during rat liver colonization. TRAIL showed deviation from this theme while showing marked induction during the early period of liver colonization (days 3 and 6 after CRC cell implantation). Riproximin exhibited substantial potential of inducing ACGs at transcriptome levels in selected CRC cell lines. Bioinformatic analysis showed that vital molecular/functional aspects of a cell are associated with the presence of ACGs.
ACGs are downregulated in primary and metastatic phase of CRC. Riproximin effectively induces ACGs in CRC cells and can be exploited for clinical investigations over time.
抗癌基因（ACGs）的异位表达对转化细胞产生抗肿瘤作用。临床上，这些基因的表达减少与癌症中的预后不良、转移和化疗/放疗耐药有关。鉴定 ACGs 的表达模式对于确定其在结直肠癌（CRC）中的预后和治疗相关性至关重要。除了临床角度外，还可以同时探索天然存在的化合物来诱导 ACGs 以实现癌细胞特异性死亡。
通过实时 PCR 鉴定 CRC 临床分离物中三种 ACGs（NOXA、PAR-4、TRAIL）的表达谱。使用微阵列方法在 CRC 肝转移动物模型中研究 ACGs 的表达变化。通过实时 PCR 在三种原发性和转移性 CRC 细胞系中鉴定纯化植物蛋白（riproximin）对选定的 ACGs 的影响。最后，通过生物信息学分析强调了 ACGs 在细胞环境中的重要性。
在将总体平均表达值与正常粘膜水平进行比较时，ACGs（除 NOXA 外）在临床分离物中持续下调。体内研究表明，在大鼠肝定植过程中，植入的 CRC 细胞中 NOXA 和 PAR-4 基因明显受到抑制。TRAIL 则偏离了这一主题，在肝定植的早期（CRC 细胞植入后第 3 天和第 6 天）表现出明显的诱导。Riproximin 在选定的 CRC 细胞系中具有诱导 ACGs 的显著潜力。生物信息学分析表明，细胞的重要分子/功能方面与 ACGs 的存在相关。
ACGs 在 CRC 的原发性和转移性阶段下调。Riproximin 可有效诱导 CRC 细胞中的 ACGs，并可随着时间的推移进行临床研究。
