Although survival outcomes of cancer patients have been improved dramatically via conventional chemotherapy and targeted therapy over the last decades, there are still some tough clinical challenges that badly needs to be overcome, such as anticancer drug resistance, inevitable recurrences, cancer progression and metastasis. Simultaneously, accumulated evidence demonstrates that aberrant glucose metabolism termed ‘the Warburg effect’ in cancer cell is closely associated with malignant phenotypes. In 2009, a novel ‘two-compartment metabolic coupling’ model, also named ‘the reverse Warburg effect’, was proposed and attracted lots of attention. Based on this new model, we consider whether this new viewpoint can be exploited for improving the existent anti-cancer therapeutic strategies. Our review focuses on the paradigm shift from ‘the Warburg effect’ to ‘the reverse Warburg effect’, the features and molecular mechanisms of ‘the reverse Warburg effect’, and then we discuss its significance in fundamental researches and clinical practice.

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Bromodomain containing 7 (BRD7) was identified as a nuclear transcriptional regulatory factor. BRD7 functions as a tumor suppressor in multiple cancers, including nasopharyngeal carcinoma (NPC). In this study, we reported a novel mechanism of BRD7 in NPC progression. We demonstrated that the expression of miR-141 was remarkably increased in NPC tissues and was negatively correlated with the expression of BRD7 and the survival rate of NPC patients. Decreased expression levels of miR-141, including the primary, the precursor and the mature forms of miR-141, were found in BRD7-overexpressing HEK293, 5-8F and HNE1 cells compared the control cells, while there was no obvious effect on the expression levels of the two critical enzymes Drosha and Dicer. BRD7 can negatively regulate the promoter activity of miR-141, while no obvious binding site of BRD7 was found in the potential promoter region of miR-141. Moreover, ectopic expression of miR-141 can significantly promote cell proliferation and inhibit apoptosis in NPC, and rescuing the expression of miR-141 in BRD7-overexpressing NPC cells could partially reverse the tumor suppressive effect of BRD7 on cell proliferation and tumor growth in vitro and in vivo. Furthermore, the activation of the PTEN/AKT pathway mediated by the overexpression of BRD7 could be inhibited by rescuing the expression of miR-141, which accordingly results in the partial restoration of cell proliferation and tumor growth. Our findings demonstrate that the BRD7/miR-141/PTEN/AKT axis has critical roles in the progression of NPC and provide some promising targets for the diagnosis and treatment of NPC.

BackgroundmiR-141 is up-regulated and plays crucial roles in nasopharyngeal carcinoma (NPC). However, the molecular mechanism underlying the dysregulation of miR-141 is still obscure.MethodsThus, the ChIP-PCR was performed to identify the c-Myc-binding sites in miR-141 and BRD7. qRT-PCR, western blot and immunohistochemistry assays were used to detect the expression of miR-141 and its up/down stream molecules. The rescue experiments on the c-Myc/miR-141 axis were performed in vitro and in vivo.ResultsOur results showed that the levels of mature miR-141, pre-miR-141 and pri-miR-141 were downregulated in c-Myc knockdown NPC cells. Meanwhile, c-Myc transactivates the expression of miR-141 by binding its promoter region. Moreover, BRD7 was identified as a co-factor of c-Myc to negatively regulate the activation of c-Myc/miR-141 axis, as well as a direct target of c-Myc. Moreover, restoration of miR-141 in c-Myc knockdown NPC cells notably rescued the effect of c-Myc on cell proliferation and tumor growth, as well as the blocking of PTEN/AKT pathway. Additionally, the expression of c-Myc was positively correlated with that of miR-141 and the clinical stages of NPC patients and negatively associated with the expression of BRD7. Our findings demonstrated that BRD7 expression and c-Myc activation forms a negative feedback loop to control the cell proliferation and tumor growth by targeting miR-141.ConclusionsThese observations provide new mechanistic insights into the dysregulation of miR-141 expression and a promising therapeutic option for NPC.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0734-2) contains supplementary material, which is available to authorized users.

Increasing evidence has shown a strong association between tumor-suppressor genes and inflammation. However, the role of BRD7 as a novel tumor suppressor in inflammation remains unknown. In this study, by observing BRD7 knockout mice for 6-12 months, we discovered that compared with BRD7 mice, BRD7 mice were more prone to inflammation, such as external inflammation and abdominal abscess. By using mouse embryo fibroblast (MEF) cells from the BRD7 knockout mouse, an in vitro lipopolysaccharide (LPS)-stimulated MEF cell line was established. The mRNA levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), chemokine (C-X-C motif) ligand 1 (CXCL-1) and inducible nitric oxide synthase (iNOS) were significantly increased in BRD7 MEF cells compared with BRD7 MEF cells after LPS stimulation for 1 or 6 h. In addition, the cytoplasm-to-nucleus translocation of nuclear factor kappa-B (NF-κB; p65) and an increased NF-κB reporter activity were observed in BRD7 MEF cells at the 1 h time point but not at the 6 h time point. Furthermore, an in vivo dextran sodium sulfate (DSS)-induced acute colitis model was created. As expected, the disease activity index (DAI) value was significantly increased in the BRD7 mice after DSS treatment for 1-5 days, which was demonstrated by the presence of a significantly shorter colon, splenomegaly and tissue damage. Moreover, higher expression levels of IL-6, TNF-α, p65, CXCL-1 and iNOS, and an increased level of NF-κB (p65) nuclear translocation were also found in the DSS-treated BRD7 mice. These findings suggest that BRD7 has an anti-inflammatory role during early acute inflammation by inhibiting activation of the NF-кB signaling pathway, which provides evidence to aid in understanding the therapeutic effects of BRD7 on inflammatory diseases.

Tumor suppressor p53 is a master regulator of apoptosis and plays key roles in cell cycle checkpoints. p53 responds to metabolic changes and alters metabolism through several mechanisms in cancer. Lactate dehydrogenase A (LDHA), a key enzyme in glycolysis, is highly expressed in a variety of tumors and catalyzes pyruvate to lactate. In the present study, we first analyzed the association and clinical significance of p53 and LDHA in breast cancer expressing wild‐type p53 (wt‐p53) and found that LDHA mRNA levels are negatively correlated with wt‐p53 but not with mutation p53 mRNA levels, and low p53 and high LDHA expression are significantly associated with poor overall survival rates. Furthermore, p53 negatively regulates LDHA expression by directly binding its promoter region. Moreover, a series of LDHA gain‐of‐function and rescore experiments were carried out in breast cancer MCF7 cells expressing endogenous wt‐p53, showing that ectopic expression of p53 decreases aerobic glycolysis, cell proliferation, migration, invasion and tumor formation of breast cancer cells and that restoration of the expression of LDHA in p53‐overexpressing cells could abolish the suppressive effect of p53 on aerobic glycolysis and other malignant phenotypes. In conclusion, our findings showed that repression of LDHA induced by wt‐p53 blocks tumor growth and invasion through downregulation of aerobic glycolysis in breast cancer, providing new insights into the mechanism by which p53 contributes to the development and progression of breast cancer.

Abstract. Breast cancer, the second most common cancer worldwide, is the leading cause of cancer-associated mortality in women, accounting for ~15% of all cancer-associated mortalities in women. The development, local invasion and metastasis of breast cancer are associated with the dysregulation and mutation of numerous genes and epigenetic mechanisms, including coding RNA and non-coding RNA, such as microRNAs (miRs/miRNAs). Previous studies have shown a dual-faced role of miR-125b in breast cancer. In the present study, a total of 221 paraffin-embedded breast cancer and 49 paraffin-embedded non-cancerous breast tissue samples were collected. In situ hybridization was used to analyze the expression of miR-125b in the breast cancer tissues. Spearman's rank correlation analysis was used to analyze the expression correlation between miR-125b and human epidermal growth factor 2 (HER2). The overall survival estimates over time were calculated using the Kaplan-Meier method with log-rank test. It was found that miR-125b expression was significantly increased in the breast cancer tissues compared with that in the non-cancerous tissues, and high miR-125b expression indicated a poor prognosis in the breast cancer patients. In addition, miR-125b expression was positively correlated with HER2, but not with progesterone receptor and estrogen receptor. Notably, high miR-125b expression was significantly correlated with tumor size and Tumor-Node-Metastasis stage in the HER2-positive breast cancer patients, along with a poor prognosis. The present study provides clinical data to confirm the oncogenic potential of miR-125b, particularly in HER2-positive human breast cancer. Thus, identification of miR-125b may be a potential molecular biomarker for the prediction of clinical outcomes in breast cancer patients, particularly HER2-positive cases that will receive paclitaxel-based neoadjuvant chemotherapy.

Our previous study demonstrated that bromodomain-containing protein 7 (BRD7) inhibits cell proliferation and tumor growth, restoring the expression of B-cell lymphoma 2 antagonist/killer (Bak) sensitized breast cancer cells to paclitaxel. However, the association between BRD7 and paclitaxel sensitization, as well as BRD7 and Bak in breast cancer remains unknown. In the present study, immunochemical staining was performed to measure the expression of BRD7 and Bak in breast cancer tissues. Cell Counting Kit-8 assay, flow cytometry and tumor xenograft procedures were performed to evaluate the biological role of BRD7 and Bak in breast cancer cells. Western blotting, reverse transcription-quantitative polymerase chain reaction, chromatin immunoprecipitation and luciferase reporter assays were also performed. BRD7 was positively correlated with Bak levels in breast cancer tissues, and the survival rate of patients with low Bak and BRD7 expression was significantly lower than that of patients with high Bak and BRD7 expression. In addition, BRD7 activated Bak promoter activity and induced Bak expression in an indirect manner. Furthermore, ectopic expression of BRD7 inhibited cell proliferation, tumor growth and sensitized cancer cells to paclitaxel, while knockdown of Bak abolished BRD7-mediated inhibitory effects on cell proliferation and paclitaxel sensitization in breast cancer cells whether in vitro and in vivo. The results demonstrated that BRD7 inhibits cell proliferation and sensitizes breast cancer cells to paclitaxel by activating Bak; they also provide promising targets for the diagnosis and treatment of breast cancer.