Kannathasan Thetchinamoorthy, Kuo Wei-Wen, Chen Ming-Cheng, Viswanadha Vijaya Padma, Shen Chia-Yao, Tu Chuan-Chou, Yeh Yu-Lan, Bharath Mahalakshmi, Shibu Marthandam Asokan, Huang Chih-Yang
Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan.
Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan.
Cancers (Basel). 2020 May 14;12(5):1231. doi: 10.3390/cancers12051231.
Guanine nucleotide-binding protein-like-3-like () is a crucial regulator of signaling that is aberrantly activated during diverse chemoresistance-associated cellular processes. However, the molecular mechanisms of tumor initiation and resistant state are largely unknown. Moreover, the identification of predictive biomarkers is necessary to effectively generate therapeutic strategies for metastatic human colorectal cancer (CRC). This study aims to identify how cells acquire resistance to anticancer drugs and whether the downregulation of miR-4454 is associated with the progression of CRC. Here, we have shown that the overexpression of miR-4454 in resistant tumors is a crucial precursor for the posttranscriptional repression of in human chemoresistant CRC progression, and we used doxycycline induced miR-4454 overexpression that significantly reduced tumor volume in a subcutaneous injection nude mice model. Together, these observations highlight that the downregulation of miR-4454 in resistant clones is prominently responsible for maintaining their resistance against anticancer drug therapy. Our study indicates that the development of miR-4454 as a microRNA-based therapeutic approach to silence may remarkably reduce oncogenic cell survival that depends on signaling, making miR-4454 a candidate for treating metastatic human CRC.
鸟嘌呤核苷酸结合蛋白样3样蛋白（）是信号传导的关键调节因子，在多种与化疗耐药相关的细胞过程中被异常激活。然而，其肿瘤起始和耐药状态的分子机制在很大程度上尚不清楚。此外，识别预测性生物标志物对于有效制定转移性人类结直肠癌（CRC）的治疗策略是必要的。本研究旨在确定细胞如何获得对抗癌药物的耐药性，以及miR - 4454的下调是否与CRC的进展相关。在这里，我们已经表明，在耐药肿瘤中miR - 4454的过表达是人类化疗耐药CRC进展中转录后抑制的关键前体，并且我们使用强力霉素诱导miR - 4454过表达，在皮下注射裸鼠模型中显著减小了肿瘤体积。总之，这些观察结果突出表明，耐药克隆中miR - 4454的下调是维持其对抗癌药物治疗耐药性的主要原因。我们的研究表明，开发基于微小RNA的治疗方法来沉默，可能会显著降低依赖信号传导的致癌细胞存活率，使miR - 4454成为治疗转移性人类CRC的候选药物。
