PKC α regulates netrin-1/UNC5B-mediated survival pathway in bladder cancer

Liu, Jiao; Kong, Chuize; Gong, Daxin; Zhang, Zhe; Zhu, Yuyan

doi:10.1186/1471-2407-14-93

Cited by 23 publications

(24 citation statements)

References 18 publications

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“…Compared to normal adjacent tissues, netrin-1 expression level was significantly higher in TCC tumors ( Fig. 1A-B), and significantly associated with the high tumor stage ( Supplementary Table 1), consistent with our previous observations on a cohort of 160 primary TCCs [17]. At mRNA level, netrin-1 expression levels were remarkably higher in the high-grade (Mann-Whitney U Test, low-grade vs. high-grade, P = 0.027, Fig.…”

Section: High Expression Of Netrin-1 Predicts a Poor Prognosis Of Tccsupporting

confidence: 91%

Therapeutic targeting Netrin-1-positive invasive bladder cancer cells with oridonin

Meng¹,

Li²,

Sun³

et al. 2020

Preprint

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Background Small compound oridonin acts as an effective anti-tumor agent used for a wide variety of human malignancies, while the antitumor efficacy and molecular mechanism of oridonin against bladder cancer remains unclear. Methods Four independent cohorts of bladder cancer were employed to assess the correlation between netrin-1 expression and progression and prognosis of bladder cancer. Clinical potential of netrin-1 as a biomarker and oridonin-mediated netrin-1-targeting anti-tumor mechanism were investigated by QRT-PCR, Western blot and ELISA. Regulatory mechanisms of Netrin-1 were investigated by luciferase reporter assay and Western blot. The EJ-inoculated nude mice xenograft model was used for the in vivo study. Results High expression of netrin-1 was significantly correlated with a poor overall survival in three independent bladder cancer cohorts. Urinary netrin-1 level was significantly elevated in bladder cancer patients correlating with tumor invasion and grade. Netrin-1 promoted cell proliferation, tumorsphere-forming, migration and invasion in bladder cancer cells. Oridonin treatment strikingly suppressed these malignant phenotypes and induced cell death in TCC cell lines and murine xenografts. Oridonin markedly decreased netrin-1 through inhibiting NF-κB transcriptional activity and shortening the half-life of NTN1 mRNA via inducing IRE1α, resulting in repression of its downstream signaling. Conclusions Together, these results strongly suggest that netrin-1 promotes the progression of bladder cancer, and acts as a potential urinary biomarker for the diagnosis as well as the prediction of the tumor progression. Oridonin exerts its strong anti-tumor activity against the invasive bladder cancer by suppressing netrin-1 mRNA production and stability.

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Section: High Expression Of Netrin-1 Predicts a Poor Prognosis Of Tccsupporting

confidence: 91%

Therapeutic targeting Netrin-1-positive invasive bladder cancer cells with oridonin

Meng¹,

Li²,

Sun³

et al. 2020

Preprint

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“…Recent studies have reported that PKC can promote the proliferation, differentiation and migration of bladder cancer cells. Thus, PKC is closely related to the biological behaviors of bladder cancer (37). Through our experiments, we found that isoquercitrin significantly reduced the expression level of phosphorylated PKC.…”

Section: Isoquercitrin-mediated Cell Cycle Arrest Of Bladder Cancer Cmentioning

confidence: 59%

Isoquercitrin inhibits bladder cancer progression in vivo and in vitro by regulating the PI3K/Akt and PKC signaling pathways

Chen

Yang

et al. 2016

Oncology Reports

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Bladder cancer is the most common malignancy of the urinary system and is also one of the 10 most common cancers of the human body. Currently, clinical treatment of bladder cancer mainly utilizes partial or total cystectomy, supplemented by conventional chemotherapy. However, such treatment has not fully improved the prognosis of patients and is associated with various side effects. Studies have found that flavonoids extracted from plants can be used in radiotherapy and chemotherapy for the prevention of postoperative recurrence and metastasis but also alone for the treatment of advanced tumors. Both applications can ameliorate clinical symptoms, improve the quality of life, and prolong the survival of patients. Based on the above information, the present study investigated the effect of isoquercitrin, a type of flavonoid found in Bidens pilosa L. extracts, on bladder cancer progression, with the goal of understanding the biological characteristics of isoquercitrin by which it participates in bladder cancer progression. Using in vitro experiments, we found that therapeutic doses of isoquercitrin significantly inhibited cell proliferation and induced apoptosis in human bladder cancer cells and that the cell cycle was arrested in the G1 phase. Isoquercitrin inhibited phosphatidylinositol 3-kinase (PI3K) and Akt phosphorylation expression levels, thus inhibiting proliferation and inducing apoptosis in the cancer cells. In addition, we found that isoquercitrin reduced protein kinase C (PKC) protein expression levels in the human bladder cancer cell lines. We also showed via in vivo experiments that isoquercitrin inhibited xenograft tumor growth in nude mice. In conclusion, our study confirmed that isoquercitrin inhibits bladder cancer progression in vivo and demonstrated that the molecular mechanism of this inhibition may be closely associated with the PI3K/Akt and PKC signaling pathways.

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“…The UNC5B receptor is down-regulated in bladder cancer tissues and is associated with bladder cancer recurrence [10]. Therefore, we hypothesized that UNC5B signaling plays a key role in the development of bladder cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Receptors of netrin-1 include DCC, the UNC5H family of proteins (UNC5A, UNC5B, UNC5C, and UNC5D) and neogenin [9]. In-depth studies of UNC5B in tumors have revealed that UNC5B is down-regulated in bladder cancer tissues and that lower UNC5B expression is an independent determinants for recurrence of bladder cancer [10]. These findings suggest that UNC5B may function as a tumor suppressor in bladder cancer.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of UNC5B in bladder cancer cells inhibits proliferation and reduces the volume of transplantation tumors in nude mice

Kong¹,

Zhan²,

Piao³

et al. 2016

BMC Cancer

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BackgroundThe netrin-1 receptor UNC5B plays vital roles in angiogenesis, inflammation, embryonic development and carcinogenesis. However, the functional significance of UNC5B overexpression in bladder cancer remains unclear. In this study, we investigated the role of UNC5B in bladder cancer in vitro and in vivo.MethodsStable transfection of the human bladder cancer cell line 5637 with UNC5B (5637-U) was confirmed by real-time RT-PCR, western blot and immunofluorescence assays. UNC5B expression in 5637 and 5637-U cells and mice tumor specimens derived from these cell lines was analyzed by immunohistochemistryand western blotting. Changes in the levels of cell cycle proteins were evaluated by western blotting. Flow cytometry, CCK-8 and scratch tests were used to examine cell cycle distribution, proliferation and migration, respectively.ResultsUNC5B overexpression in 5637 cells inhibited cell multiplication and migration and induced cell cycle arrest at the G2/M phase, meanwhile exhibited changes in the expression of cell cycle-associated proteins, showing that UNC5B may inhibit metastatic behaviors in bladder cancer cells. In addition, tumors generated from 5637-U cells were smaller than tumors generated from control 5637 cells.ConclusionsOur findings suggest that UNC5B is a potential anti-neoplastic target in bladder cancer progression.

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PKC α regulates netrin-1/UNC5B-mediated survival pathway in bladder cancer

Cited by 23 publications

References 18 publications

Therapeutic targeting Netrin-1-positive invasive bladder cancer cells with oridonin

Therapeutic targeting Netrin-1-positive invasive bladder cancer cells with oridonin

Isoquercitrin inhibits bladder cancer progression in vivo and in vitro by regulating the PI3K/Akt and PKC signaling pathways

Overexpression of UNC5B in bladder cancer cells inhibits proliferation and reduces the volume of transplantation tumors in nude mice

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