Background: Esophageal cancer (EC) is the eighth most common cancer and the sixth most common cause of death worldwide. Esophageal squamous cell carcinoma (ESCC) comprises the majority of esophageal cancers globally, and 5-Fluorouraci (5-FU) is one of the commonly used chemotherapeutics for this type of cancer. Chemoresistance to drugs is a main obstacle in the successful treatment of this malignancy. Methods: In this study, we used the CRISPR/Cas9 screening method to determine the target gene related to 5-FU drug resistance in esophageal cancer. Results: Our research findings indicate that the loss of PFKFB3 can increase the resistance of different human esophageal squamous cell carcinoma cell lines to 5-FU through various pathways. Specifically, in KYSE-70 cells, loss of PFKFB3 can induce epithelial–mesenchymal transition (EMT) and prolong the S phase of the cell cycle, allowing cancer cells to evade the effects of 5-FU and develop resistance. In the KYSE-270 and KYSE-150 cell lines, loss of PFKFB3 can upregulate the expression of Slug and Mcl-1, indirectly regulate Chk1 and promote its autophosphorylation, which in turn inhibits apoptosis, thus counteracting the effects of 5-FU. Conclusions: Our research not only enriches our understanding of the biological characteristics of different ESCC cell lines but also provides new clinical insights for future personalized treatments. Assessing the status of PFKFB3 can help predict resistance to 5-FU in ESCC patients with different genetic backgrounds, allowing for more precise treatment planning. This personalized approach has the potential to improve treatment efficacy, reduce unnecessary drug use and side effects, and ultimately improve patient survival rates and quality of life.
背景：食管癌是全球第八大常见癌症和第六大常见死亡原因。食管鳞状细胞癌占全球食管癌的大多数，5-氟尿嘧啶是该类癌症常用化疗药物之一。药物化疗耐药性是成功治疗该恶性肿瘤的主要障碍。方法：本研究采用CRISPR/Cas9筛选技术鉴定食管癌中与5-FU耐药相关的靶基因。结果：研究发现PFKFB3缺失可通过不同途径增强多种人食管鳞癌细胞系对5-FU的耐药性。具体而言，在KYSE-70细胞中，PFKFB3缺失可诱导上皮-间质转化并延长细胞周期S期，使癌细胞逃避5-FU作用而产生耐药；在KYSE-270和KYSE-150细胞系中，PFKFB3缺失能上调Slug和Mcl-1表达，间接调控Chk1并促进其自磷酸化，进而抑制细胞凋亡，从而抵消5-FU的作用。结论：本研究不仅深化了对不同ESCC细胞系生物学特性的认识，更为未来个体化治疗提供了新的临床思路。通过评估PFKFB3状态，可帮助预测不同遗传背景ESCC患者对5-FU的耐药性，从而制定更精准的治疗方案。这种个体化诊疗策略有望提高治疗效果，减少不必要的药物使用和副作用，最终提升患者生存率和生活质量。
肿瘤(癌症)患者之家