Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital & Institute, 100142, Beijing, China.
School of Science, Technology and Engineering, University of the Sunshine Coast, Maroochydore DC, Sunshine Coast, QLD, 4556, Australia.
Cell Death Dis. 2023 Jul 13;14(7):425. doi: 10.1038/s41419-023-05956-0.
Estrogen plays a protective role in colorectal cancer (CRC) and primarily functions through estrogen receptor β (ERβ). However, clinical strategies for CRC therapy associated with ERβ are still under investigation. Our discoveries identified WFDC3 as a tumor suppressor that facilitates estrogen-induced inhibition of metastasis through the ERβ/TGFBR1 signaling axis. WFDC3 interacts with ERβ and increases its protein stability by inhibiting its proteasome-dependent degradation. WFDC3 represses TGFBR1 expression through ERβ-mediated transcription. Blocking TGFβ signaling with galunisertib, a drug used in clinical trials that targets TGFBR1, impaired the migration of CRC cells induced by WFDC3 depletion. Moreover, there was clinical significance to WFDC3 in CRC, as CRC patients with high WFDC3 expression in tumor cells had favorable prognoses. Therefore, this work suggests that WFDC3 could be an indicator for therapies targeting the estrogen/ERβ pathway in CRC patients.
雌激素在结直肠癌（CRC）中发挥保护作用，主要通过雌激素受体β（ERβ）发挥作用。然而，与 ERβ 相关的 CRC 治疗的临床策略仍在研究中。我们的发现确定 WFDC3 是一种肿瘤抑制因子，通过 ERβ/TGFBR1 信号轴促进雌激素诱导的转移抑制。WFDC3 与 ERβ 相互作用，并通过抑制其蛋白酶体依赖性降解来增加其蛋白质稳定性。WFDC3 通过 ERβ 介导的转录抑制 TGFBR1 的表达。用 galunisertib（一种用于临床试验靶向 TGFBR1 的药物）阻断 TGFβ 信号，削弱了 WFDC3 耗尽诱导的 CRC 细胞迁移。此外，WFDC3 在 CRC 中具有临床意义，因为肿瘤细胞中 WFDC3 表达高的 CRC 患者预后良好。因此，这项工作表明，WFDC3 可能是 CRC 患者针对雌激素/ERβ 通路治疗的标志物。
