Subjects: Biology >> Biophysics >> Oncology submitted time 2016-05-12
Huang, Zhaohui
Zhang, Binbin
Quan, Cao
Bian, Zehua
Hua, Dong
Huang, Zhaohui
Cheng, Haipeng
Chen, Xiaoping
Fushimi, Kazuo
Wu, Jane Y.
Wen, Pushuai
Kong, Ruirui
Chen, Mengmeng
Liu, Jianghong
Zhu, Li
Wu, Jane Y.
Zhang, Zhenfeng
Du, Xiang
Abstract： Originally discovered in neuronal guidance, the Slit-Robo pathway is emerging as an important player in human cancers. However, its involvement and mechanism in colorectal cancer (CRC) remains to be elucidated. Here, we report that Slit2 expression is reduced in CRC tissues compared with adjacent noncancerous tissues. Extensive promoter hypermethylation of the Slit2 gene has been observed in CRC cells, which provides a mechanistic explanation for the Slit2 downregulation in CRC. Functional studies showed that Slit2 inhibits CRC cell migration in a Robo-dependent manner. Robo-interacting ubiquitin-specific protease 33 (USP33) is required for the inhibitory function of Slit2 on CRC cell migration by deubiquitinating and stabilizing Robo1. USP33 expression is downregulated in CRC samples, and reduced USP33 mRNA levels are correlated with increased tumor grade, lymph node metastasis and poor patient survival. Taken together, our data reveal USP33 as a previously unknown tumor-suppressing gene for CRC by mediating the inhibitory function of Slit-Robo signaling on CRC cell migration. Our work suggests the potential value of USP33 as an independent prognostic marker of CRC.
Peer Review Status:
Awaiting Review
Subjects: Biology >> Biophysics submitted time 2016-05-11
Kong, Ruirui
Wen, Pushuai
Liu, Jianghong
Zhu, Li
Wu, Jane Y.
Yi, Fengshuang
Ren, Jinqi
Feng, Wei
Yi, Fengshuang
Chen, Xiaoping
Wu, Jane Y.
Li, Xiaofei
Nie, Yongzhan
Wu, Kaichun
Fan, Daiming
Zhu, Li
Nie, Yongzhan
Wu, Kaichun
Fan, Daiming
Zhu, Li
Abstract： Emerging evidence indicates that the neuronal guidance molecule SLIT plays a role in tumor suppression, as SLIT-encoding genes are inactivated in several types of cancer, including lung cancer; however, it is not clear how SLIT functions in lung cancer. Here, our data show that SLIT inhibits cancer cell migration by activating RhoA and that myosin 9b (Myo9b) is a ROBO-interacting protein that suppresses RhoA activity in lung cancer cells. Structural analyses revealed that the RhoGAP domain of Myo9b contains a unique patch that specifically recognizes RhoA. We also determined that the ROBO Intracellular domain interacts with the Myo9b RhoGAP domain and inhibits its activity; therefore, SLIT-dependent activation of RhoA is mediated by ROBO inhibition of Myo9b. In a murine model, compared with control lung cancer cells, SLIT-expressing cells had a decreased capacity for tumor formation and lung metastasis. Evaluation of human lung cancer and adjacent nontumor tissues revealed that Myo9b is upregulated in the cancer tissue. Moreover, elevated Myo9b expression was associated with lung cancer progression and poor prognosis. Together, our data identify Myo9b as a key player in lung cancer and as a ROBO-interacting protein in what is, to the best of our knowledge, a newly defined SLIT/ROBO/Myo9b/RhoA signaling pathway that restricts lung cancer progression and metastasis. Additionally, our work suggests that targeting the SLIT/ROBO/Myo9b/RhoA pathway has potential as a diagnostic and therapeutic strategy for lung cancer.
Peer Review Status:Awaiting Review
Subjects: Biology >> Biophysics >> Cell Biology submitted time 2016-05-11
Tu, Tao
Yan, Huiwen
Luo, Yongting
Ye, Zhongde
Chen, Jianan
Feng, Jing
Yan, Xiyun
Zhang, Chunxia
Liu, Feng
Kong, Ruirui
Wen, Pushuai
Wu, Jane Y.
Wu, Jane Y.
Abstract： Angiogenesis, a process that newly-formed blood vessels sprout from pre-existing ones, is vital for vertebrate development and adult homeostasis. Previous studies have demonstrated that the neuronal guidance molecule netrin-1 participates in angiogenesis and morphogenesis of the vascular system. Netrin-1 exhibits dual activities in angiogenesis: either promoting or inhibiting angiogenesis. The anti-angiogenic activity of netrin-1 is mediated by UNC5B receptor. However, how netrin-1 promotes angiogenesis remained unclear. Here we report that CD146, an endothelial transmembrane protein of the immunoglobulin superfamily, is a receptor for netrin-1. Netrin-1 binds to CD146 with high affinity, inducing endothelial cell activation and downstream signaling in a CD146-dependent manner. Conditional knockout of the cd146 gene in the murine endothelium or disruption of netrin-CD146 interaction by a specific anti-CD146 antibody blocks or reduces netrin-1-induced angiogenesis. In zebrafish embryos, downregulating either netrin-1a or CD146 results in vascular defects with striking similarity. Moreover, knocking down CD146 blocks ectopic vascular sprouting induced by netrin-1 overexpression. Together, our data uncover CD146 as a previously unknown receptor for netrin-1 and also reveal a functional ligand for CD146 in angiogenesis, demonstrating the involvement of netrin-CD146 signaling in angiogenesis during vertebrate development.
Peer Review Status:Awaiting Review
Hits
Hits
Downloads
Comment