Hubei Province Key Laboratory on Cardiovascular, Cerebrovascular and Metabolic Disorders, Hubei University of Science and Technology, Xianning 437100, China.
Department of Physiology, School of Basic Medical Sciences, Hubei University of Science and Technology, Xianning 437100, China.
Acta Biochim Biophys Sin (Shanghai). 2018 Jun 1;50(6):597-604. doi: 10.1093/abbs/gmy040.
Although doxorubicin has become a key drug in cancer treatment, the resistance of colorectal carcinoma to doxorubicin is a major problem in clinical practice. F-box and WD repeat domain-containing 7 (FBXW7) plays important roles in human cancers and is one of the major causes of drug resistance. The miR-223/FBXW7 pathway has been reported to be a crucial clue to the mechanism of chemoresistance in many human cancers, such as gastric cancer, breast cancer, and non-small cell lung cancer. However, it is unclear whether similar mechanisms of doxorubicin resistance are involved in colorectal cancer (CRC). The aim of the current study was to evaluate the role of miR-223/FBXW7 pathway in chemosensitivity in different CRC cell lines and to investigate the relevant underlying mechanisms. We found that high levels of FBXW7 expression were associated with increased doxorubicin sensitivity in different CRC cell lines, and FBXW7 was regulated by miR-223. Overexpression of miR-223 decreased FBXW7 expression and the sensitivity of CRC cells to doxorubicin, while suppression of miR-223 had the opposite effect. Moreover, epithelial-mesenchymal transition (EMT) was proved to be regulated by miR-223/FBXW7 pathway and involved in the drug resistance. In conclusion, miR-223/FBXW7 axis regulates doxorubicin sensitivity through EMT in CRC, which may lead to the development of individualized treatment in clinical practice.
尽管阿霉素已成为癌症治疗的关键药物，但结直肠癌对阿霉素的耐药性是临床实践中的一个主要问题。F-box 和 WD 重复结构域包含 7 号（FBXW7）在人类癌症中发挥重要作用，是导致耐药性的主要原因之一。miR-223/FBXW7 通路已被报道是许多人类癌症（如胃癌、乳腺癌和非小细胞肺癌）中化疗耐药机制的关键线索。然而，miR-223/FBXW7 通路是否参与结直肠癌（CRC）的耐药机制尚不清楚。本研究旨在评估 miR-223/FBXW7 通路在不同 CRC 细胞系中对化疗敏感性的作用，并探讨相关的潜在机制。我们发现，不同 CRC 细胞系中 FBXW7 表达水平较高与阿霉素敏感性增加相关，而 FBXW7 受 miR-223 调控。miR-223 的过表达降低了 FBXW7 的表达和 CRC 细胞对阿霉素的敏感性，而 miR-223 的抑制则产生相反的效果。此外，上皮-间充质转化（EMT）被证明受 miR-223/FBXW7 通路调控，并参与耐药性。总之，miR-223/FBXW7 轴通过 EMT 调节 CRC 中的阿霉素敏感性，这可能导致临床实践中个体化治疗的发展。
