Huang Wen-Shih, Wu Kuen-Lin, Chen Cheng-Nan, Chang Shun-Fu, Lee Ding-Yu, Lee Ko-Chao
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
Division of Colon and Rectal Surgery, Department of Surgery, Chiayi Chang Gung Memorial Hospital, Chiayi 613, Taiwan.
Biology (Basel). 2024 Oct 14;13(10):821. doi: 10.3390/biology13100821.
Colorectal cancer (CRC) has become a prevalent and deadly malignancy over the years. Drug resistance remains a major challenge in CRC treatment, significantly affecting patient survival rates. Obesity is a key risk factor for CRC development, and accumulating evidence indicates that increased secretion of adipokines, including Visfatin, under obese conditions contributes to the development of resistance in CRC to various therapeutic methods. Amphiregulin (AREG) is a member of the epidermal growth factor (EGF) family, which activates the EGF receptor (EGFR), influencing multiple tumorigenic characteristics of cancers. Abnormal expression levels of AREG in cancer cells have been associated with resistance to anti-EGFR therapy in patients. However, it remains unclear whether this abnormal expression also impacts CRC resistance to other chemotherapeutic drugs. The aim of this study is to examine whether AREG expression levels could be affected in CRC cells under Visfatin stimulation, thereby initiating the development of resistance to 5-fluororacil (5-FU). Through our results, we found that Visfatin indeed increases AREG expression, reducing the sensitivity of HCT-116 CRC cells to 5-FU cytotoxicity. Moreover, AREG upregulation is regulated by STAT3-CREB transcription factors activated by JNK1/2 and p38 signaling. This study highlights the significant role of AREG upregulation in CRC cells in initiating chemotherapeutic resistance to 5-FU under Visfatin stimulation. These findings provide a deeper understanding of drug resistance development in CRC under obese conditions and offer new insights into the correlation between an abnormal increase in AREG levels and the development of 5-FU-resistance in CRC cells, which should be considered in future clinical applications.
近年来，结直肠癌（CRC）已成为一种常见且致命的恶性肿瘤。耐药性仍然是CRC治疗中的一个主要挑战，严重影响患者的生存率。肥胖是CRC发生的一个关键风险因素，越来越多的证据表明，在肥胖条件下，包括内脂素在内的脂肪因子分泌增加，会导致CRC对各种治疗方法产生耐药性。双调蛋白（AREG）是表皮生长因子（EGF）家族的成员，它激活EGF受体（EGFR），影响癌症的多种致瘤特性。癌细胞中AREG的异常表达水平与患者对抗EGFR治疗的耐药性有关。然而，尚不清楚这种异常表达是否也会影响CRC对其他化疗药物的耐药性。本研究的目的是探讨在内脂素刺激下，CRC细胞中AREG的表达水平是否会受到影响，从而引发对5-氟尿嘧啶（5-FU）的耐药性。通过我们的研究结果，我们发现内脂素确实会增加AREG的表达，降低HCT-116 CRC细胞对5-FU细胞毒性的敏感性。此外，AREG的上调受JNK1/2和p38信号激活的STAT3-CREB转录因子调控。本研究强调了AREG上调在CRC细胞中在内脂素刺激下引发对5-FU化疗耐药性方面的重要作用。这些发现为肥胖条件下CRC耐药性的发展提供了更深入的理解，并为AREG水平异常升高与CRC细胞中5-FU耐药性发展之间的相关性提供了新的见解，这在未来的临床应用中应予以考虑。
