Disheveled3 通过 Wnt/β-catenin/c-Myc/SOX2 通路增强结直肠癌细胞的 EMT 和癌症干细胞样细胞特性。
Disheveled3 enhanced EMT and cancer stem-like cells properties via Wnt/β-catenin/c-Myc/SOX2 pathway in colorectal cancer.
机构信息
Oncology Department of Chengdu Seventh People's Hospital, Chengdu, China.
School of Biological Sciences and Technology, Chengdu Medical College, Chengdu, 610500, China.
出版信息
J Transl Med. 2023 May 5;21(1):302. doi: 10.1186/s12967-023-04120-8.
BACKGROUND
Epithelial-to-mesenchymal transition (EMT) and cancer stem-like cells (CSLCs) play crucial role in tumor metastasis and drug-resistance. Disheveled3 (DVL3) is involved in malignant behaviors of cancer. However, the role and potential mechanism of DVL3 remain elusive in EMT and CSLCs of colorectal cancer (CRC).
METHODS
UALCAN and PrognoScan databases were employed to evaluate DVL3 expression in CRC tissues and its correlation with CRC prognosis, respectively. Transwell, sphere formation and CCK8 assay were used to assess metastasis, stemness and drug sensitivity of CRC cells, respectively. Western blotting and dual luciferase assay were performed to analyze the protein expression and Wnt/β-catenin activation, respectively. Lentiviral transfection was used to construct the stable cell lines. Animal studies were performed to analyze the effect of silencing DVL3 on tumorigenicity and metastasis of CRC cells in vivo.
RESULTS
DVL3 was overexpressed in CRC tissues and several CRC cell lines. DVL3 expression was also higher in CRC tissues with lymph node metastasis than tumor tissues without metastasis, and correlated with poor prognosis of CRC patients. DVL3 positively regulated the abilities of migration, invasion and EMT-like molecular changes in CRC cells. Moreover, DVL3 promoted CSLCs properties and multidrug resistance. We further identified that Wnt/β-catenin was crucial for DVL3-mediated EMT, stemness and SOX2 expression, while silencing SOX2 inhibited DVL3-mediated EMT and stemness. Furthermore, c-Myc, a direct target gene of Wnt/β-catenin, was required for SOX2 expression and strengthened EMT and stemness via SOX2 in CRC cells. Finally, knockdown of DVL3 suppressed tumorigenicity and lung metastasis of CRC cells in nude mice.
CONCLUSION
DVL3 promoted EMT and CSLCs properties of CRC via Wnt/β-catenin/c-Myc/SOX2 axis, providing a new strategy for successful CRC treatment.
背景
上皮间质转化（EMT）和癌症干细胞样细胞（CSLCs）在肿瘤转移和耐药中起着至关重要的作用。Disheveled3（DVL3）参与了癌症的恶性行为。然而，DVL3 在结直肠癌（CRC）中的 EMT 和 CSLCs 中的作用和潜在机制仍不清楚。
方法
使用 UALCAN 和 PrognoScan 数据库分别评估 CRC 组织中 DVL3 的表达及其与 CRC 预后的相关性。Transwell、球体形成和 CCK8 测定分别用于评估 CRC 细胞的转移、干性和药物敏感性。Western blot 和双荧光素酶报告基因检测分别用于分析蛋白表达和 Wnt/β-catenin 激活。慢病毒转染用于构建稳定的细胞系。动物研究用于分析沉默 DVL3 对 CRC 细胞体内致瘤性和转移的影响。
结果
DVL3 在 CRC 组织和几种 CRC 细胞系中过表达。DVL3 的表达在有淋巴结转移的 CRC 组织中也高于无转移的肿瘤组织，并且与 CRC 患者的不良预后相关。DVL3 正向调节 CRC 细胞的迁移、侵袭和 EMT 样分子变化能力。此外，DVL3 促进 CSLCs 特性和多药耐药性。我们进一步确定 Wnt/β-catenin 对 DVL3 介导的 EMT、干性和 SOX2 表达至关重要，而沉默 SOX2 抑制了 DVL3 介导的 EMT 和干性。此外，Wnt/β-catenin 的直接靶基因 c-Myc，是 CRC 细胞中 SOX2 表达所必需的，并且通过 SOX2 增强 EMT 和干性。最后，沉默 DVL3 抑制了裸鼠 CRC 细胞的致瘤性和肺转移。
结论
DVL3 通过 Wnt/β-catenin/c-Myc/SOX2 轴促进 CRC 的 EMT 和 CSLCs 特性，为成功治疗 CRC 提供了新策略。
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