Liang Yunan, Lin Han, Jiang Zongsheng, Zhao Qi, Cui Ri, Li Shaotang
Department of Colorectal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang Street, Ouhai District, Wenzhou, 325000, Zhejiang, China.
Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Chashan Road, Wenzhou, 325035, Zhejiang, China.
Discov Oncol. 2024 Oct 29;15(1):603. doi: 10.1007/s12672-024-01440-z.
Homeobox B8 (HOXB8) belongs to the HOX family and was essential to the development of colorectal carcinoma. Among the prevalent monoclonal antibodies for treating RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients, cetuximab stands out, but resistance to cetuximab frequently arises in targeted treatments. Currently, the role of HOXB8 in cetuximab-resistant mCRC remains unclear. By comparing drug-sensitive cell lines (SW48) with drug-resistant cell lines (HCT116, CACO2), we discovered that HOXB8 was substantially expressed in cetuximab-resistant cell lines, and furthermore, in drug-resistant cell lines (HCT116, CACO2), HOXB8 knockdown increased the cytotoxicity of cetuximab via blocking the signal transducer and activator of transcription 3 (STAT3) signaling pathway. Conversely, the excessive expression of HOXB8 reduced the growth suppression in SW48 cells caused by cetuximab by triggering the STAT3 signaling pathway. Conclusively, we conclude that HOXB8 has played an essential role in cetuximab-resistant mCRC and that treating HOXB8 specifically may be a useful treatment approach for certain cetuximab-resistant mCRC patients.
同源盒B8（HOXB8）属于HOX家族，对结直肠癌的发展至关重要。在用于治疗RAS/BRAF野生型转移性结直肠癌（mCRC）患者的常见单克隆抗体中，西妥昔单抗脱颖而出，但在靶向治疗中经常出现对西妥昔单抗的耐药性。目前，HOXB8在西妥昔单抗耐药的mCRC中的作用仍不清楚。通过比较药物敏感细胞系（SW48）和耐药细胞系（HCT116、CACO2），我们发现HOXB8在西妥昔单抗耐药细胞系中大量表达，此外，在耐药细胞系（HCT116、CACO2）中，敲低HOXB8可通过阻断信号转导和转录激活因子3（STAT3）信号通路增加西妥昔单抗的细胞毒性。相反，HOXB8的过度表达通过触发STAT3信号通路降低了西妥昔单抗对SW48细胞生长的抑制作用。总之，我们得出结论，HOXB8在西妥昔单抗耐药的mCRC中起重要作用，特异性治疗HOXB8可能是某些西妥昔单抗耐药的mCRC患者的一种有效治疗方法。
