Abstract
The human DEAD/H-box RNA helicase DDX6 (RCK/p54) is a protein encoded by the fusion gene from the t(11;14)(q23;q32) chromosomal translocation observed in human B-cell lymphoma cell line RC-K8. DDX6 has a variety of functions such as translation initiation, pre-mRNA splicing, and ribosome assembly. However, details of the regulatory mechanism governing DDX6 and the functions of DDX6 are largely unknown. Previously, we reported that DDX6 is overexpressed in most malignant cell lines and clinical colorectal tumor samples and that DDX6 positively contributes to the pathogenesis of various cancers. In the current study, we aimed at revealing the function of DDX6 in HER2 and FGFR2 related human gastric cancer (GC) by using clinical samples and GC cell lines. DDX6 protein was overexpressed in about 60% of the clinical samples; HER2, in 35%; and FGFR2, in 30%, (n = 20). Interestingly, the DDX6 protein was overexpressed in all HER2-positive samples (n = 7), and in 83% (5 of 6) of the FGFR2-positive samples, which could reflect the contribution of DDX6 to the expression of HER2 and FGFR2. In the GC cell line MKN7, which has HER2 amplification, the knockdown of DDX6 by siR-DDX6 led to the decreased expression of the HER2 protein. On the other hand, the knockdown of HER2 did not influence the DDX6 expression. Similar results were also obtained for the KATO-III and HSC39 cell lines having amplified FGFR2 expression. The increased expression of DDX6 induced a significantly increased expression of the HER2 protein without increasing the mRNA expression. The results of an RNP Immunoprecipitation (RIP)-assay using GC cells indicated that the DDX6 protein acted as an RNA-binding protein for HER2 and FGFR2 mRNAs and positively regulated their post-transcriptional processes. These findings demonstrated that DDX6 was an upstream molecule that positively regulated the expression of HER2 and FGFR2 at the post-transcriptional step in GC cells.
Highlights
Gastric cancer (GC) is the fifth most common cancer and third most common cause of cancer-related deaths worldwide
The expression levels of DDX6, HER2, and FGFR2 in these samples were increased in 12 (60%), 7 (35%), and 6 (30%) samples, respectively; 9 of 10 (90%) patients with the high expression levels of FGFR2 and/or HER2 showed DDX6 overexpression (Figure 1B). These results suggested to us that RNA helicase DDX6 may be related to the expression of HER2 and FGFR2
We investigated the expression levels of DDX6, HER2, and FGFR2 in TMK1, MKN7, MKN74, MKN45, F2R, NUGC3, NUGC3/5-FU, NUGC4, HSC39, and KATO-III cells by using Western blotting (Figure 1A)
Summary
Gastric cancer (GC) is the fifth most common cancer and third most common cause of cancer-related deaths worldwide. More than 720,000 deaths are attributed to GC annually [1]. GC is diagnosed in its early stages owing to improvements in endoscopy. In chemotherapy against GC, we use traditional drugs, such as 5-fluorouracil, cisplatin, and taxans, as well as molecular targeting drugs, such as trastuzumab (an anti-human epidermal growth factor receptor 2 (HER2) antibody) and ramucirumab (the anti-vascular endothelial growth factor receptor 2 (VEGFR2) monoclonal antibody). The efficacy of chemotherapy for advanced or recurrent GC is not satisfactory because the median survival time of patients having undergone chemotherapy without an immune checkpoint inhibitor is reported to be only 6 to 13 months in some trials [4]. There is a need for the identification of new therapeutic target molecules and novel biomarkers for individualized therapy and early diagnosis. No molecular targets for GC therapy have yet been suggested
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