Abstract
BackgroundGolgin-97 is a tethering factor in the trans-Golgi network (TGN) and is crucial for vesicular trafficking and maintaining cell polarity. However, the significance of golgin-97 in human diseases such as cancer remains unclear.MethodsWe searched for a potential role of golgin-97 in cancers using Kaplan-Meier Plotter (http://kmplot.com) and Oncomine (www.oncomine.org) datasets. Specific functions of golgin-97 in migration and invasion were examined in golgin-97-knockdown and golgin-97-overexpressing cells. cDNA microarray, pathway analysis and qPCR were used to identify gene profiles regulated by golgin-97. The role of golgin-97 in NF-κB signaling pathway was examined by using subcellular fractionation, luciferase reporter assay, western blot analysis and immunofluorescence assay (IFA).ResultsWe found that low expression of golgin-97 correlated with poor overall survival of cancer patients and was associated with invasiveness in breast cancer cells. Golgin-97 knockdown promoted cell migration and invasion, whereas re-expression of golgin-97 restored the above phenotypes in breast cancer cells. Microarray and pathway analyses revealed that golgin-97 knockdown induced the expression of several invasion-promoting genes that were transcriptionally regulated by NF-κB p65. Mechanistically, golgin-97 knockdown significantly reduced IκBα protein levels and activated NF-κB, whereas neither IκBα levels nor NF-κB activity was changed in TGN46- or GCC185-knockdown cells. Conversely, golgin-97 overexpression suppressed NF-κB activity and restored the levels of IκBα in golgin-97-knockdown cells. Interestingly, the results of Golgi-disturbing agent treatment revealed that the loss of Golgi integrity was not involved in the NF-κB activation induced by golgin-97 knockdown. Moreover, both TGN-bound and cytosolic golgin-97 inhibited NF-κB activation, indicating that golgin-97 functions as an NF-κB suppressor regardless of its subcellular localization.ConclusionOur results collectively demonstrate a novel and suppressive role of golgin-97 in cancer invasiveness. We also provide a new avenue for exploring the relationship between the TGN, golgin-97 and NF-κB signaling in tumor progression.
Highlights
Golgin-97 is a tethering factor in the trans-Golgi network (TGN) and is crucial for vesicular trafficking and maintaining cell polarity
We provide a new avenue for exploring the relationship between the TGN, golgin-97 and NF-κB signaling in tumor progression
Based on the Oncomine database, we found that golgin-97 mRNA levels in ductal breast carcinoma and large cell lung carcinoma were significantly lower than those in normal tissues (Fig. 1b, 1.5fold change with a p-value less than 0.05)
Summary
Golgin-97 is a tethering factor in the trans-Golgi network (TGN) and is crucial for vesicular trafficking and maintaining cell polarity. The four mammalian GRIP domain proteins differ in their membrane-binding properties and are recruited to distinct domains of the TGN [12]. Both golgin-97 and golgin-245 act as scaffold molecules and are recruited onto the TGN by interacting with Arf-like protein 1 (Arl1) , an Arf small GTPase family member in the Ras superfamily, to establish a molecular platform required for numerous distinct processes of vesicle transport [2, 6,7,8, 13,14,15]. The roles of these GRIP domain golgins in human diseases remain unclear
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