<em>CUL4A</em> promotes cell invasion in gastric cancer by activating the NF-&kappa;B signaling pathway

Abstract

Cullin 4A (CUL4A) overexpression has been reported to be involved in the carcinogenesis and progression of many malignant tumors. However, the role of CUL4A in the progression of gastric cancer (GC) remains unclear. In this study, we explored whether and how CUL4A regulates proinflammatory signaling to promote GC cell invasion. Our results showed that knockdown of CUL4A inhibited GC cell migration and invasion induced by lipopolysaccharide (LPS) stimulation. We also found that both CUL4A and nuclear factor-kappa B (NF-κB) protein expressions were enhanced by LPS stimulation in HGC27 GC cell lines. Furthermore, knockdown of CUL4A decreased the protein expression of NF-κB and mRNA expression of the downstream genes of the NF-κB pathway, such as matrix metalloproteinase (MMP) 2, MMP9, and interleukin-8. Our immunohistochemistry analysis on 50 GC tissue samples also revealed that CUL4A positively correlated with NF-κB expression. Taken together, our findings suggest that CUL4A may promote GC cell invasion by regulating the NF-κB signaling pathway and could be considered as a potential therapeutic target in patients with GC.

CUL4A regulates endometrial cancer cell proliferation, invasion and migration by interacting with CSN6

“…Increasing evidence has suggested that uncontrolled proliferation, invasion and migration are dominant features of cancer cells, which exert crucial effects in the development process of human cancer (26,27). In the present study, notably upregulated CUL4A expression was observed in EC cells, and CUL4A-knockdown refrained EC cell proliferation, invasion and migration, which was consistent with previous studies (28,29). Taken together, these results indicated that CUL4A-knockdown serves protective roles in EC.…”

The emerging role for Cullin 4 family of E3 ligases in tumorigenesis

“…CUL4A and CUL4B are both targets of LEF/TCF transcription factors of the canonical Wnt signaling) 101 Overexpression of CUL4A leads to initiation and progression of lung cancer in mice [89][90][91] . Consistently, numerous pathological studies have detected upregulation of CUL4A in various human cancer specimens, such as gastric cancer [102][103][104] , breast cancer [104][105][106] , colorectal cancer 104,[107][108][109] and lung cancer 93,110,111 , which is also negatively correlated with prognostic survival 93,110,111,[112][113][114][115][116] . As the core component of the CRL4 complex, the tumorigenic effects of CUL4A overexpression mainly depend on its interactions with downstream targets (details will be discussed in subsequent sections), which trigger cell cycle progression and/or epithelial mesenchymal transition, leading to tumor proliferation, invasion or drug resistance 106,107,117 .…”

“…Lung cancer initiation and progression (transgenic overexpression of Cul4a) [89][90][91] ;Resistant to UV-induced skin carcinogenesis (skin-specific knockout of Cul4a) 55 Overexpressed in multiple myeloma 310 , cholangiocarcinoma 113,114 , gastric cancer [102][103][104] , colorectal cancer 104,[107][108][109] , ovarian cancer 104,112,311 , lung cancer 93,110,111 , breast cancer [104][105][106] , osteosarcoma 312,313 , hepatocellular cancer 117,314 , malignant pleural mesothelioma 315,316 , pituitary adenoma 317 , prostate cancer 318 CUL4B Oncogenic Spontaneous development of liver cancer (transgenic overexpression of Cul4b) 92 Overexpressed in cholangiocarcinoma 120 , pancreatic carcinoma 119 , lung cancer 93 • 118 , colorectal cancer 115,116 , glioma 319 , liver cancer 122 , cervical cancer 121 290,325 HBx Hepatocarcinogenesis in transgenic Hbx mice 129,130 Overexpressed in liver cancer…”

NF-κB in Gastric Cancer Development and Therapy

“…Several other cellular factors, which contribute to the progression of gastric carcinoma through modulating the NF-κB signaling have been described and include Cullin 4A [ 64 ], TNF [ 65 ], stomach-specific protein gastrokine 1 (GKN1) [ 66 ], interleukin 17A [ 67 ], IL-1β polymorphisms [ 68 ], cytoskeleton protein radixin [ 69 ], fibroblast growth factor-inducible 14 (Fn14) [ 70 ], inhibitor of growth 4 (ING4) [ 71 ], trefoil factor 1 (TFF1) [ 72 ], connective tissue growth factor (CTGF) [ 73 ], carcinoembryonic antigen-related cell adhesion molecule 19 (CEACAM19) [ 74 ], DNA repair protein (Ku) [ 75 ], stress protein metallothionein 2A (MT2A) [ 76 ], deacetylase sirtuin 1 (SIRT1) [ 77 ], oncogenes latent membrane protein 1 (LMP1) and LMP2A [ 78 ], microRNAs [ 79 , 80 , 81 , 82 ], or spermine oxidase [ 83 ].…”