Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
Department of Urology, Affiliated Dalian Friendship Hospital of Dalian Medical University, China.
FEBS Open Bio. 2020 Oct;10(10):2107-2121. doi: 10.1002/2211-5463.12964. Epub 2020 Sep 16.
Lemur tyrosine kinase 3 (LMTK3) is a key member of the serine-threonine tyrosine kinase family. It plays an important role in breast cancer tumorigenesis and progression. However, its biological role in bladder cancer remains elusive. In this study, we demonstrated that LMTK3 was overexpressed in bladder cancer and was positively correlated with bladder cancer malignancy. High LMTK3 expression predicted poor overall survival. Knockdown of LMTK3 in bladder cancer cells triggered cell-cycle arrest at G2/M phase, suppressed cell growth, and induced cell apoptosis in bladder cancer cells. Furthermore, Transwell assays revealed that reduction of LMTK3 decreased cell migration by regulating the epithelial-to-mesenchymal transition pathway. Conversely, LKTM3 overexpression was shown to promote proliferation and migration of bladder cancer cells. We assessed phosphorylation of MEK and ERK1/2 in bladder cancer cells depleted of LMTK3 and demonstrated a reduced phosphorylation status compared with the control group. Using an MAPK signaling-specific inhibitor, U0126, we could rescue the promotion of proliferation and viability in LMTK3-overexpressing cells. In conclusion, we extend the status of LMTK3 as an oncogene in bladder cancer and provide evidence for its function via the activation of the ERK/MAPK pathway. Thus, targeting LMTK3 may hold potential as a diagnostic and prognostic biomarker and as a possible future treatment for bladder cancer.
Lemur 酪氨酸激酶 3（LMTK3）是丝氨酸-苏氨酸-酪氨酸激酶家族的关键成员。它在乳腺癌的发生和发展中发挥着重要作用。然而，其在膀胱癌中的生物学作用仍不清楚。在本研究中，我们证明了 LMTK3 在膀胱癌中过表达，并且与膀胱癌的恶性程度呈正相关。高 LMTK3 表达预示着总体生存率较差。在膀胱癌细胞中敲低 LMTK3 会触发细胞周期在 G2/M 期停滞，抑制细胞生长，并诱导膀胱癌细胞凋亡。此外，Transwell 测定显示，通过调节上皮间质转化途径，降低 LMTK3 的表达会减少细胞迁移。相反，LMTK3 的过表达被证明能促进膀胱癌细胞的增殖和迁移。我们评估了 LMTK3 耗尽的膀胱癌细胞中 MEK 和 ERK1/2 的磷酸化状态，并与对照组相比显示出磷酸化状态降低。使用 MAPK 信号通路特异性抑制剂 U0126，我们可以挽救 LMTK3 过表达细胞中增殖和活力的促进作用。总之，我们将 LMTK3 作为膀胱癌中的癌基因的状态进行了扩展，并通过激活 ERK/MAPK 通路提供了其功能的证据。因此，靶向 LMTK3 可能作为膀胱癌的诊断和预后生物标志物，并可能成为未来膀胱癌的一种治疗方法。
