Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences.
Center for Innovative Clinical Medicine, Okayama University Hospital.
Acta Med Okayama. 2022 Apr;76(2):203-215. doi: 10.18926/AMO/63425.
The epithelial-mesenchymal transition (EMT), a normal biological process by which epithelial cells acquire a mesenchymal phenotype, is associated with migration, metastasis, and chemoresistance in cancer cells, and with poor prognosis in patients with esophageal cancer. However, therapeutic strategies to inhibit EMT in tumor environments remain elusive. Here, we show the therapeutic potential of telomerase-specific replication- competent oncolytic adenovirus OBP-301 in human esophageal cancer TE4 and TE6 cells with an EMT phenotype. Transforming growth factor-β (TGF-β) administration induced the EMT phenotype with spindleshaped morphology, upregulation of mesenchymal markers and EMT transcription factors, migration, and chemoresistance in TE4 and TE6 cells. OBP-301 significantly inhibited the EMT phenotype via E1 accumulation. EMT cancer cells were susceptible to OBP-301 via massive autophagy induction. OBP-301 suppressed tumor growth and lymph node metastasis of TE4 cells co-inoculated with TGF-β-secreting fibroblasts. Our results suggest that OBP-301 inhibits the TGF-β-induced EMT phenotype in human esophageal cancer cells. OBP-301-mediated E1A overexpression is a promising antitumor strategy to inhibit EMT-mediated esophageal cancer progression.
上皮-间充质转化（EMT）是一种正常的生物学过程，上皮细胞在此过程中获得间充质表型，与癌细胞的迁移、转移和化疗耐药有关，并与食管癌患者的预后不良有关。然而，抑制肿瘤微环境中 EMT 的治疗策略仍然难以捉摸。在这里，我们展示了端粒酶特异性复制有效的溶瘤腺病毒 OBP-301 在具有 EMT 表型的人食管癌细胞 TE4 和 TE6 中的治疗潜力。转化生长因子-β（TGF-β）给药诱导 EMT 表型，具有梭形形态、间充质标志物和 EMT 转录因子上调、迁移和 TE4 和 TE6 细胞的化疗耐药性。OBP-301 通过 E1 积累显著抑制 EMT 表型。EMT 癌细胞通过大量自噬诱导易受 OBP-301 影响。OBP-301 抑制了与分泌 TGF-β 的成纤维细胞共接种的 TE4 细胞的肿瘤生长和淋巴结转移。我们的结果表明，OBP-301 抑制了人食管癌细胞中 TGF-β 诱导的 EMT 表型。OBP-301 介导的 E1A 过表达是抑制 EMT 介导的食管癌进展的有前途的抗肿瘤策略。
