Overexpression of Cullin4A correlates with a poor prognosis and tumor progression in esophageal squamous cell carcinoma

Nakade, Hiroshi; Migita, Kazuhiro; Matsumoto, Sohei; Wakatsuki, Kohei; Kunishige, Tomohiro; Miyao, Shintaro; Sho, Masayuki

doi:10.1007/s10147-019-01547-2

Cited by 8 publications

(14 citation statements)

References 28 publications

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“…Formalin-fixed, paraffin-embedded tissues were cut into 5 µm-thick-sections. Sections were stained using a DAKO EnVision system (Dako; Agilent Technologies, Inc.), as described previously ( 16 , 23 , 24 ). Mouse monoclonal anti-RBX1 antibody (cat.…”

Section: Methodsmentioning

confidence: 99%

“…no. 4368813; Applied Biosystems; Thermo Fisher Scientific, Inc.) as previously described ( 16 , 23 , 24 ). For RT-qPCR, cDNA was amplified using TaqMan Fast Universal PCR Master Mix (2X; Applied Biosystems; Thermo Fisher Scientific, Inc.) with gene-specific primers and a lysate probe on a StepOnePlus Real-Time PCR System (Applied Biosystems; Thermo Fisher Scientific, Inc.), according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…In transfection analyses, TE-1 and TE-6 cells were seeded in 6-well plates and transfected with either control RNA (scrambled siRNA; Qiagen, Inc.) or siRNA (20 nmol) against RBX1. Transfection was performed using the Lipofectamine ® system (Invitrogen; Thermo Fisher Scientific), as described previously ( 16 , 23 , 24 ). The human RBX1 siRNA duplexes, generated with 3′-dTdT overhangs and prepared by Qiagen, Inc, were used to target the following DNA sequence: 5′-CTGCTGTTACCTAATTACAAA-3′.…”

Section: Methodsmentioning

confidence: 99%

“…Cell viability assay. Cell viability was determined using a Cell-Titer Blue ® Cell Viability Assay kit (Promega Corporation), as described previously (16,23,24). Briefly, aliquots of 3.0x10 3 TE-1 cells and 4.0x10 3 TE-6 cells per well were cultured in 96-well plates at 37˚C.…”

Section: Methodsmentioning

confidence: 99%

“…Cell cycle analysis. Cell cycle analysis was performed using a Cycletest™ Plus DNA Reagent kit (BD Biosciences), as described previously (16,23,24). Cells were stained with propidium iodide at 4˚C for 15 min using the Cycletest™ Plus DNA Reagent kit (cat.…”

Section: Methodsmentioning

confidence: 99%

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Ring box protein-1 is associated with a poor prognosis and tumor progression in esophageal cancer

et al. 2020

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Ring box protein-1 (RBX1) is an essential component of the S-phase kinase-associated protein, Cullin and F-box containing ubiquitin ligases. Overexpression of RBX1 has been reported in several cancer types; however, little is known regarding the prognostic value and role of RBX1 in esophageal cancer. The present study examined 120 patients with esophageal cancer (EC) who underwent curative esophagectomy and 61 patients with EC who underwent neoadjuvant combination chemotherapy with docetaxel, cisplatin and 5-fluorouracil (5-FU; DCF) using immunohistochemistry. All specimens were classified into two groups according to the percentage of RBX1-positive tumor cells. In addition, the impact of RBX1 expression on cancer cell proliferation was analyzed in vitro using a small interfering RNA silencing technique. RBX1 expression levels showed significant differences according to tumor size (P<0.001), tumor depth (P=0.002), lymph node metastasis (P=0.004), pathological stage (P=0.001), lymphatic invasion (P=0.001) and venous invasion (P=0.001). The overall survival (OS) rate in the RBX1 high expression group was significantly lower compared with that in the low group (P=0.004). Multivariate analysis demonstrated that RBX1 status was an independent prognostic factor. RBX1 gene silencing inhibited the proliferation of human EC cells and enhanced the antitumor effect of 5-FU. Among patients who underwent neoadjuvant DCF therapy, the RBX1 high expression group had a significantly lower OS rate compared with that of the RBX1-low group (P<0.001). In conclusion, RBX1 has notable prognostic value, and RBX1 may serve an important function in the tumor progression of EC.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Ring box protein-1 is associated with a poor prognosis and tumor progression in esophageal cancer

et al. 2020

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Analysis of multiple programmed cell death-related prognostic genes and functional validations of necroptosis-associated genes in oesophageal squamous cell carcinoma

Cao,

Zhu,

et al. 2024

eBioMedicine

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Targeted CUL4A inhibition synergizes with cisplatin to yield long-term survival in models of head and neck squamous cell carcinoma through a DDB2-mediated mechanism

et al. 2022

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Patients with late-stage and human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) continue to have a very poor prognosis. The development of more effective novel therapies that improve overall survival and overcome drug resistance is an urgent priority. Here we report that HNSCC tumors significantly overexpress NEDD8 and exhibit high sensitivity to the first-in-class NEDD8-activating enzyme (NAE) inhibitor pevonedistat. Additional studies established that disruption of NEDD8-mediated protein turnover with pevonedistat dramatically augmented cisplatin-induced DNA damage and apoptosis in HNSCC models. Further analysis revealed that the specific pevonedistat target CUL4A played an essential role in driving the synergy of the pevonedistat and cisplatin combination. Targeted inhibition of CUL4A resulted in significant downregulation in Damage Specific DNA binding protein 2 (DDB2), a DNA-damage recognition protein that promotes nucleotide excision repair and resistance to cisplatin. Silencing of CUL4A or DDB2 enhanced cisplatin-induced DNA damage and apoptosis in a manner similar to that of pevonedistat demonstrating that targeted inhibition of CUL4A may be a novel approach to augment cisplatin therapy. Administration of pevonedistat to mice bearing HNSCC tumors significantly decreased DDB2 expression in tumor cells, increased DNA damage and potently enhanced the activity of cisplatin to yield tumor regression and long-term survival of all animals. Our findings provide strong rationale for clinical investigation of CUL4A inhibition with pevonedistat as a novel strategy to augment the efficacy of cisplatin therapy for patients with HNSCC and identify loss of DDB2 as a key pharmacodynamic mediator controlling sensitivity to this regimen.

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Overexpression of Cullin4A correlates with a poor prognosis and tumor progression in esophageal squamous cell carcinoma

Cited by 8 publications

References 28 publications

Ring box protein-1 is associated with a poor prognosis and tumor progression in esophageal cancer

Ring box protein-1 is associated with a poor prognosis and tumor progression in esophageal cancer

Analysis of multiple programmed cell death-related prognostic genes and functional validations of necroptosis-associated genes in oesophageal squamous cell carcinoma

Targeted CUL4A inhibition synergizes with cisplatin to yield long-term survival in models of head and neck squamous cell carcinoma through a DDB2-mediated mechanism

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