TRIM44 promotes cell proliferation and migration by inhibiting FRK in renal cell carcinoma

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Proliferation ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Lymphatic Invasion ◽  
Cancer Specific Survival ◽  
Candidate Target ◽  
Candidate Target Gene ◽  
And Migration

TRIM44 has oncogenic roles in various cancers. However, TRIM44 expression andits function in renal cell carcinoma (RCC) are still unknown. Here in this study, weinvestigated the clinical significance of TRIM44 and its biological function in RCC.TRIM44 overexpression was significantly associated with clinical M stage, histologictype (clear cell) and presence of lymphatic invasion (P = .047, P = .005, and P = .028,respectively). Moreover, TRIM44 overexpression was significantly associated withpoor prognosis in terms of cancer-specific survival (P = .019). Gain-of-function andloss-of-function studies using TRIM44 and siTRIM44 transfection showed thatTRIM44 promotes cell proliferation and cell migration in two RCC cell lines, Caki1and 769P. To further investigate the role of TRIM44 in RCC, we performed integratedmicroarray analysis in Caki1 and 769P cells and explored the data in the Oncominedatabase. Interestingly, FRK was identified as a promising candidate target gene ofTRIM44, which was downregulated in RCC compared with normal renal tissues. Wefound that cell proliferation was inhibited by TRIM44 knockdown and then recoveredby siFRK treatment. Taken together, the present study revealed the associationbetween high expression of TRIM44 and poor prognosis in

scholarly journals lncRNA 00312 Attenuates Cell Proliferation and Invasion and Promotes Apoptosis in Renal Cell Carcinoma via miR-34a-5p/ASS1 Axis

2020 ◽  
Vol 2020 ◽  
pp. 1-16 ◽  
Author(s):  
Jiawei Zeng ◽  
Yuanmeng Li ◽  
Yaodong Wang ◽  
Gang Xie ◽  
Qian Feng ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Proliferation ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Functional Roles ◽  
Normal Tissues ◽  
Potential Binding Site ◽  
Proliferation And Invasion

Background. Previous studies have demonstrated that lncRNAs play functional roles in regulating cancer cell proliferation, invasion, and apoptosis. Recent studies confirmed that lncRNA 00312 has important biological functions in lung and colorectal cancer. However, the role of lncRNA 00312 in renal cell carcinoma (RCC) remains unclear. Our aim was to explore the function of lncRNA 00312 in RCC and its potential molecular mechanism. Methods. RCC cell lines A498 and ACHN were used as in vitro models in this study. RT-PCR was performed to determine lncRNA 00312, miR-34a-5p, and ASS1 mRNA expression. Proliferation and invasion were examined by CCK-8 and Transwell assay to confirm the function role of lncRNA 00312. Western blot analysis was used to examine the expression of apoptotic proteins Bax and Bcl-2. Results. lncRNA was significantly downregulated in RCC cells such as A498 and ACHN; the expression of lncRNA 00312 in RCC tissues was significantly lower than that in adjacent normal tissues. Patients with low expression of lncRNA 00312 have worse prognosis regarding pathological grade, tumor size, and TNM stage. Overexpression of lncRNA 00312 suppressed A498 and ACHN cell proliferation and invasion, while promoting apoptosis. Our study found that miR-34a-5p had the potential binding site with lncRNA 00312 and revealed the role of miR-34a-5p in RCC. Furthermore, we confirmed that lncRNA 00312 played its role with the participation of ASS1 and miR-34a-5p. Conclusion. lncRNA 00312 can inhibit RCC proliferation and invasion and promote apoptosis in vitro by suppressing miR-34a-5p and overexpressing ASS1. Our study demonstrated that the lncRNA 00312/miR-34a-5p/ASS1 axis may play a functional role in the progression of RCC; lncRNA 00312 abundance is a prognostic factor candidate for RCC survival, which provides new insights for RCC clinical treatment.

scholarly journals Neuropilin 1 and Neuropilin 2 Gene Invalidation or Pharmacological Inhibition Reveals Their Relevance for the Treatment of Metastatic Renal Cell Carcinoma

2020 ◽  
Author(s):  
Aurore Dumond ◽  
Etienne Brachet ◽  
Jérôme Durivault ◽  
Valérie Vial ◽  
Anna K. Puszko ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Proliferation ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Dependent Manner ◽  
Cell Renal Cell Carcinoma ◽  
Immunodeficient Mice ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

Abstract Background: Despite the improvement of relapse-free survival mediated by anti-angiogenic drugs like sunitinib (Sutent ®), or by combinations of anti-angiogenic drugs with immunotherapy, metastatic clear cell Renal Cell Carcinoma (mccRCC) remain incurable. Hence, new relevant treatments are urgently needed. The VEGFs coreceptors, Neuropilins 1, 2 (NRP1, 2) are expressed on several tumor cells including ccRCC. We analysed the role of the VEGFs/NRPs signaling in ccRCC aggressiveness and evaluated the relevance to target this pathway.Methods: We correlated the NRP1, 2 levels to patients’ survival using online available data base. Human and mouse ccRCC cells were knocked-out for the NRP1 and NRP2 genes by a CRISPR/Cas9 method. Their proliferation and migration were evaluated by XTT or impedance tests and by wound closure. Production of VEGFA and VEGFC was evaluated by ELISA. Experimental ccRCC were performed in immuno-competent/deficient mice. The effects of a competitive inhibitor of NRP1, 2, NRPa-308, was tested in vitro and in vivo with the above-mentioned tests and on experimental ccRCC. NRPa-308 docking on both NRPs was performed.Results: Invalidation of the NRP1 and NRP2 genes inhibited cell proliferation and migration and stimulated the expression of VEGFA or VEGFC, respectively. NRPa-308 presented a higher affinity for NRP2 than for NRP1. It decreased cell proliferation and migration more efficiently than sunitinib and the commercially available NRP inhibitor EG00229. NRPa-308 presented a robust inhibition of experimental ccRCC growth in immunocompetent and immunodeficient mice in a reverse dose dependent manner. Such inhibition was associated with a decreased expression of several pro-tumoral factors. Analysis of the TCGA database showed that NRP2, more than NRP1 correlates with tumor aggressiveness only in metastatic patients.Conclusion: Our study strongly suggests that inhibiting NRP is a good therapeutic strategy for mccRCC patients in therapeutic impasses and NRPa-308 represents a relevant hit.

scholarly journals Interleukin-33 Predicts Poor Prognosis and Promotes Renal Cell Carcinoma Cell Growth Through its Receptor ST2 and the JNK Signaling Pathway

2018 ◽  
Vol 47 (1) ◽  
pp. 191-200 ◽  
Author(s):  
Chang-wen Wu ◽  
Yi-guo Wu ◽  
Cheng Cheng ◽  
Zheng-dong Hong ◽  
Zi-min Shi ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Flow Cytometry ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Cell Carcinoma ◽  
Western Blotting ◽  
Renal Cell ◽  
Jnk Signaling

Background/Aims: Renal cell carcinoma (RCC) is currently the ninth most common cancer in men. Interleukin (IL)-33 expression has previously been associated with a number of cancers; however, its biological role in RCC is poorly understood. In this study, we sought to elucidate the role of IL-33 in RCC. Methods: Serum IL-33 levels were measured by ELISA. IL-33 expression in clinical RCC samples was examined by immunocytochemistry. The proliferation and apoptosis rate of RCC were determined by CCK8 and flow cytometry. Mcl1 and Bcl-2 expression were measured by quantitative real-time PCR and western blotting. JNK expression were measured by western blotting and flow cytometry. The in vivo role of IL-33 in RCC tumorigenesis was examined by animal models. Results: We found that increased expression of IL-33 in RCC was associated with tumor-lymph node-metastasis (TNM) stage and inversely correlated with prognosis. IL-33 enhances RCC cell growth in vivo and stimulates RCC cell proliferation and prevents chemotherapy-induced tumor apoptosis in vitro. Furthermore, we demonstrated that IL-33 promotes RCC cell proliferation and chemotherapy resistance via its receptor ST2 and the JNK signaling activation in tumor cells. Conclusion: Our findings suggest that targeting IL-33/ST2 and JNK signaling may have potential value in the treatment of RCC.

scholarly journals Bim Expression in Peritumoral Lymphocytes is Associated with Survival in Patients with Metastatic Clear Cell Renal Cell Carcinoma

Kidney Cancer ◽  
2021 ◽  
pp. 1-7
Author(s):  
Bimal Bhindi ◽  
Elizabeth Bearrick ◽  
John C. Cheville ◽  
Christine M. Lohse ◽  
Ross J. Mason ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Cancer Specific Survival ◽  
Immunohistochemistry Staining ◽  
Multivariable Adjustment

Background: Bim (BCL-2-interacting mediator of cell death) is a downstream pro-apoptotic signaling molecule activated by the PD-1 pathway. Objective: We sought to determine if Bim expression in peritumoral T-lymphocytes (PTLs) is associated with survival in patients with metastatic clear cell renal cell carcinoma (ccRCC). Methods: Immunohistochemistry staining for Bim was performed on paraffin-embedded tumor tissue blocks from patients with metastatic ccRCC who underwent nephrectomy between 1990-2004. Associations of Bim expression with cancer-specific survival (CSS) and overall survival (OS) from date of metastasis were evaluated using multivariable Cox regression models, adjusting for age, sex, and metastases-score. Results: 525 patients with metastatic ccRCC, of whom 169 (32%) had metastases at time of nephrectomy were studied. After multivariable adjustment, high Bim expression remained associated with worse CSS (HR = 1.31; 95%CI 1.07–1.59; p = 0.008) and OS (HR = 1.28; 95%CI 1.06–1.55; p = 0.01). The interaction between Bim and PD-L1 was not statistically significant for CSS (p = 0.68) or OS (p = 0.57), suggesting that the associations between Bim and survival outcomes were not significantly different based on tumor PD-L1 expression. Conclusion: High Bim expression in PTLs at nephrectomy is prognostic of worse CSS and OS in patients with metastatic ccRCC, irrespective of tumor PD-L1 expression. The role of earlier PD-1/PD-L1-directed therapy warrants evaluation in these patients.

scholarly journals Aberrant MEK5 Signalling Promotes Renal Cancer Development via mTOR Activation

2021 ◽  
Author(s):  
Fangzhou Li ◽  
Xu Feng Peng ◽  
Jiale Zhou ◽  
Qi Chen ◽  
Yonghui Chen
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Proliferation ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Mtor Signaling Pathway ◽  
Wound Healing Assay ◽  
Normal Tissues ◽  
Oncomine Database ◽  
And Migration ◽  
Favorable Safety

Abstract Purpose: Renal cell carcinoma is one of the most incident malignancies globally. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma. However, comprehensive clinical treatment has some limitations. Therefore, exploring the pathogenesis and identifying novel therapeutic targets are required urgently. MEK5 has been reported to play an essential role in the development of various cancers. However, no study has evaluated its role and specific mechanisms in ccRCC. Methods: Using the ONCOMINE database, MEK5 expression in ccRCC and normal tissues was compared. ccRCC and adjacent normal tissues were collected from fourteen ccRCC patients, and ccRCC expression was assessed by qPCR and immunohistochemistry. MEK5 overexpression and knockdown plasmids were constructed and transfected into ccRCC cells. CCK8, wound-healing assay, and clone formation assay were performed to examine the cell proliferation, migration, and clone formation ability of ccRCC cells. Furthermore, a western blot was performed to verify the regulation and influence of MEK5 on the mTOR signaling pathway. The MEK5 small molecule inhibitor BIX was used to treat cells, followed by CCK8, wound-healing assay, clone formation, and flow cytometry assay to examine the cell proliferation, migration, clone formation ability, apoptosis, and cell cycle. Finally, a murine subcutaneous tumor model was constructed, and the effect and safety of BIX were evaluated in-vivo.Results: The ONCOMINE database indicated that the MEK5 expression in ccRCC was significantly higher than the normal tissues, further confirmed in clinical specimens. The knockdown of MEK5 markedly inhibited the ability of ccRCC cell proliferation, colony formation, and migration. In contrast, MEK5 overexpression promoted cell proliferation, colony formation, and migration. Western blotting showed that overexpression of MEK5 can further activate the mTOR signaling pathway. The MEK5 inhibitor, BIX treatment of ccRCC, significantly inhibited cell proliferation, arrested the cell cycle in the G0/G1 phase, induced apoptosis, and effectively inhibited cell migration and clone formation. BIX also showed an excellent anti-tumor effect and favorable safety profile in murine models.Conclusions: MEK5 regulated the mTOR signal pathway and regulated the cell proliferation, cycle, migration, clone formation of ccRCC. Targeted inhibition of MEK5 had a good anti-tumor effect and favorable safety profile, providing new directions for ccRCC therapy.

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