Endothelial Delta-like 4 (DLL4) promotes renal cell carcinoma hematogenous metastasis

Huang, Qing; Ma, Xin; Li, Hong Zhao; Ai, Qing; Liu, Shang Wen; Yu, Zhuang; Gao, Yu; Yang, Fan; Ni, Dong; Wang, Bao Jun; Zhang, Xu

doi:10.18632/oncotarget.1827

Cited by 34 publications

(24 citation statements)

References 32 publications

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“…Therefore, the expression levels of DLL4, Six1, Notch 1 and Twist 1 were also determined in this study, and the results indicated that HDAC5 increased the expression of DLL4, Six1, Notch 1 and Twist 1 in the A549 cells. Our results were in line with the results from previous studies that found that overexpression of DLL4 was associated with poor outcomes of patients with pancreatic adenocarcinoma, and elevated DLL4 promoted renal carcinoma cell metastasis (26,27). Thus, we may speculate that elevated HDAC5 promotes the expression of DLL4 in lung cancer, and contributes to poor patient outcomes and metastasis.…”

Section: Discussionsupporting

confidence: 92%

Histone deacetylase�5 promotes the proliferation and invasion of lung cancer cells

et al. 2018

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Histone deacetylase 5 (HDAC5), as a member of the class IIa family of HDACs, is frequently dysregulated in human malignancies. However, little is known regarding the specific role of HDAC5 in lung cancer. We aimed to evaluate HDAC5 expression in human lung cancer and to determine the effects of HDAC5 on lung cancer cells. First, the expression levels of both HDAC5 protein and mRNA were evaluated in lung cancer tissues and cell lines by western blot analysis and RT‑qPCR, and the results suggested that HDAC5 was significantly upregulated in human lung cancer tissues and cell lines. To address the effects of HDAC5 on the biological behavior of human lung adenocarcinoma cells, we generated human lung cancer A549 cell lines in which HDAC5 was either overexpressed or depleted. The results indicated that overexpression of HDAC5 significantly promoted the proliferation and invasion, and inhibited the apoptosis of A549 cells. On the contrary, HDAC5 knockdown largely decreased the proliferation and invasion and enhanced the apoptosis of A549 cells. Furthermore, we demonstrated that HDAC5 overexpression promoted the expression of DLL4, Six1, Notch 1 and Twist 1 in A549 cells. Downregulation of HDAC5 caused a significant inhibition of the expression of DLL4, Six1, Notch 1 and Twist 1 in A549 cells. Taken together, our data demonstrated that HDAC5 displayed a significant upregulation in lung cancer, and elevated HDAC5 might be involved in the potentiation of proliferation and invasion of lung cancer cells, as well as the inhibition of lung cancer cell apoptosis by the upregulation of DLL4, Six1, Notch 1 and Twist 1. The present study may provide an evidence for the potential application of HDAC5 inhibitors in the therapy of lung cancer.

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Section: Discussionsupporting

confidence: 92%

Histone deacetylase�5 promotes the proliferation and invasion of lung cancer cells

et al. 2018

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“…1E). Moreover, previous study reported that DLL4 could promote RCC cell migration and invasion by activating intercellular Notch signaling 31 . Data in the UALCAN database revealed that mRNA expression of DLL4 were significantly higher in RCC tissues than in normal tissues in pan-cancer analysis ( Supplementary Fig.…”

Section: B Cells Induced Hif-2α Upregulation Activated Dll4 To Initiamentioning

confidence: 97%

Tumor-educated B cells promote renal cancer metastasis via inducing the IL-1β/HIF-2α/Notch1 signals

Huang

et al. 2020

Cell Death Dis

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While B cells in the tumor microenvironment (TME) might play important roles in cancer progression, their impacts on the renal cell carcinoma (RCC) metastasis remained unclear, which drew our attention to further explore. We found that RCC tissues could recruit more B cells than the surrounding normal renal tissues from human clinical RCC samples. Wound healing assay, transwell assay and 3D invasion assays demonstrated that recruited B cells, also known as tumor-educated B cells (TEB), could significantly increase the RCC cell migration and invasion. In addition, in vivo data from xenograft RCC mouse model also confirmed that TEB could enhance RCC cell invasive and metastatic capability. Mechanism dissection revealed that TEB activated IL-1β/HIF-2α signals in RCC cells that could induce the downstream Notch1 signaling pathway. The above results demonstrated the key roles of TEB within renal cancer associated tumor microenvironment were metastasis-promotor and might help us to develop the potential therapies via targeting these newly identified IL-1β/HIF-2α/Notch1 signals in RCC progression.

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“…Western blot assays were performed as previously described (19). The information on all primary antibodies is listed in Supplementary Table S1.…”

Section: Western Blot Assaymentioning

confidence: 99%

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

Gao

et al. 2017

Cancer Research

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The transcription factor KLF6 has an essential role in the development and metastasis of multiple human cancers. Paradoxically, KLF6 expression was found to be attenuated in primary metastatic clear cell renal cell carcinoma (ccRCC), such that it is unclear how KLF6 affects malignant progression in this setting. In this study, we demonstrate that KLF6 attenuation in renal cells is sufficient to promote E2F1-mediated epithelialmesenchymal transition and metastatic prowess. In a mouse xenograft model of human ccRCC, silencing KLF6 increased tumor cell proliferation and malignant character, whereas E2F1 silencing reversed these properties. These effects were corroborated in a metastatic model system, where we observed a greater number of pulmonary metastatic lesions formed by ccRCC cells where KLF6 was silenced and E2F1 enforced. Analysis of clinical specimens of ccRCC revealed that low levels of KLF6 and high levels of E2F1 correlated closely with ccRCC development. Overall, our results established the significance of activating the KLF6-E2F1 axis in aggressive ccRCC, defining a novel critical signaling mechanism that drives human ccRCC invasion and metastasis. Cancer Res; 77(2); 330-42. Ó2016 AACR.

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Endothelial Delta-like 4 (DLL4) promotes renal cell carcinoma hematogenous metastasis

Cited by 34 publications

References 32 publications

Histone deacetylase�5 promotes the proliferation and invasion of lung cancer cells

Histone deacetylase�5 promotes the proliferation and invasion of lung cancer cells

Tumor-educated B cells promote renal cancer metastasis via inducing the IL-1β/HIF-2α/Notch1 signals

KLF6 Suppresses Metastasis of Clear Cell Renal Cell Carcinoma via Transcriptional Repression of E2F1

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