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Background: 3-Hydroxy butyrate dehydrogenase 2 (BDH2) is a short-chain dehydrogenase/reductase family member that plays a key role in the development and pathogenesis of human cancers. However, the role of BDH2 in gastric cancer (GC) remains largely unclear. Our study aimed to ascertain the regulatory mechanisms of BDH2 in GC, which could be used to develop new therapeutic strategies. Methods: Western blotting, immunohistochemistry, and RT-PCR were used to investigate the expression of BDH2 in GC specimens and cell lines. Its correlation with the clinicopathological characteristics and prognosis of GC patients was analysed. Functional assays, such as CCK-8 and TUNEL assays, transmission electron microscopy, and an in vivo tumour growth assay, were performed to examine the proliferation, apoptosis, and autophagy of GC cells. Related molecular mechanisms were clarified by luciferase reporter, coimmunoprecipitation, and ubiquitination assays. Results: BDH2 was markedly downregulated in GC tissues and cells, and the low expression of BDH2 was associated with poor survival of GC patients. Functionally, BDH2 overexpression significantly induced apoptosis and autophagy in vitro and in vivo. Mechanistically, BDH2 promoted Keap1 interaction with Nrf2 to increase the ubiquitination level of Nrf2. Ubiquitination/degradation of Nrf2 inhibited the activity of ARE to increase accumulation of reactive oxygen species (ROS), thereby inhibiting the phosphorylation levels of Akt Ser473 and mTOR Ser2448. Conclusions: Our study indicates that BDH2 is an important tumour suppressor in GC. BDH2 regulates intracellular ROS levels to mediate the PI3K/Akt/mTOR pathway through Keap1/Nrf2/ARE signalling, thereby inhibiting the growth of GC.

The mechanism by which miR‐605‐3p regulates hepatocellular carcinoma (HCC) metastasis has not been clarified. In this study, we found that miR‐605‐3p was down‐regulated in HCC and that low miR‐605‐3p expression was associated with tumour thrombus and tumour satellites. HCC patients with low miR‐605‐3p expression showed shorter overall survival and disease‐free survival after surgery. Overexpression of miR‐605‐3p inhibited epithelial‐mesenchymal transition and metastasis of HCC through NF‐κB signalling by directly inhibiting expression of TRAF6 , while silencing of miR‐605‐3p had the opposite effect. We also found that SNHG16 directly bound to miR‐605‐3p as a competing endogenous RNA. Mechanistically, high expression of SNHG16 promoted binding to miR‐605‐3p and inhibited its activity, which led to up‐regulation of TRAF6 and sustained activation of the NF‐κB pathway, which in turn promoted epithelial‐mesenchymal transition and metastasis of HCC. TRAF6 increased SNHG16 promoter activity by activating NF‐κB, thereby promoting the transcriptional expression of SNHG16 and forming a positive feedback loop that aggravated HCC malignancy. Our findings reveal a mechanism for the sustained activation of the SNHG16 / miR‐605‐3p / TRAF6 /NF‐κB feedback loop in HCC and provide a potential target for a new HCC treatment strategy.

Peripheral blood lymphocyte subsets have been reported to be useful as prognostic and/or diagnostic markers for patients with cancer. However, the clinical value of peripheral blood lymphocyte subsets in gastric cancer (GC) has remained elusive. In the present study, peripheral CD3 + , CD4 + and CD8 + T lymphocytes, B cells (CD19 + ), regulatory T cells (Tregs; CD4 + CD25 + CD127 - ) and natural killer (NK) cells (CD3 - CDl6 + CD56 + ) were detected by flow cytometry in 122 patients with GC, 80 healthy donors (HDs) and 80 patients with gastric ulcer (GU). NK cells (CD56 + ) were detected by immunohistochemical (IHC) analysis in 20 GC and three GU tissue samples. A receiver-operating characteristic (ROC) curve was used to determine the threshold of the peripheral NK cell level and survival analysis was performed to assess its prognostic value in patients with GC. The results indicated that the peripheral NK cell proportion in patients with GC (18.77%) was significantly higher than that in the HD (12.19%) and GU (12.74%) groups. IHC analysis suggested that the NK level in GC tumor samples was correlated with that in paired serum samples. ROC curve analysis indicated that the peripheral NK cell level (15.16%) was able to effectively identify patients with GC, a diagnostic sensitivity of 75.41% and a specificity of 77.45% were determined. Multivariate logistic regression analysis revealed that the peripheral NK cell level was independently associated with the T stage and survival analysis demonstrated that high levels of peripheral NK cells were associated with poor prognosis of patients with GC. In conclusion, the peripheral NK cell level may be a diagnostic and prognostic marker for patients with GC.