The switch of cellular metabolism from mitochondrial respiration to glycolysis is the hallmark of cancer cells and associated with tumor malignancy. However, the mechanism of this metabolic switch remains largely unknown. Herein, we reported that hypoxia-inducible factor-1 (HIF-1) induced pyruvate dehydrogenase kinase-3 (PDK3) expression leading to inhibition of mitochondrial respiration. Promoter activity assay, small interference RNA knockdown assay, and chromatin immunoprecipitation assay demonstrated that hypoxia-induced PDK3 gene activity was regulated by HIF-1 at the transcriptional level. Forced expression of PDK3 in cancer cells resulted in increased lactic acid accumulation and drugs resistance, whereas knocking down PDK3 inhibited hypoxia-induced cytoplasmic glycolysis and cell survival. These data demonstrated that increased PDK3 expression due to elevated HIF-1␣ in cancer cells may play critical roles in metabolic switch during cancer progression and chemoresistance in cancer therapy.

Transforming growth factor-␤1 (TGF-␤1)-induced epithelial-to-mesenchymal transition (EMT) contributes to the pathophysiological development of kidney fibrosis. Although it was reported that TGF-␤1 enhances ␤ 1 integrin levels in NMuMG cells , the detailed molecular mechanisms underlying TGF-␤1-induced ␤ 1 integrin gene expression and the role of ␤ 1 integrin during EMT in the renal system are still unclear. In this study , we examined the role of ␤ 1 integrin in TGF-␤1-induced EMT both in vitro and in vivo. TGF-␤1-induced augmentation of ␤ 1 integrin expression was required for EMT in several epithelial cell lines, and knockdown of Smad3 inhibited TGF-␤1-induced augmentation of ␤ 1 integrin. TGF-␤1 triggered ␤ 1 integrin gene promoter activity as assessed by luciferase activity assay. Both knockdown of Smad3 and mutation of the Smad-binding element to block binding to the ␤ 1 integrin promoter markedly reduced TGF-␤1-induced ␤ 1 integrin promoter activity. Chromatin immunoprecipitation assay showed that TGF-␤1 enhanced Smad3 binding to the ␤ 1 integrin promoter. Furthermore, induction of unilateral ureteral obstruction triggered increases of ␤ 1 integrin in both renal epithelial and interstitial cells. In human kidney with chronic tubulointerstitial fibrosis, we also found a concomitant increase of ␤ 1 integrin and ␣-smooth muscle actin in tubule epithelia. Blockade of ␤ 1 integrin signaling dampened the progression of fibrosis. Taken together, ␤ 1 integrin mediates EMT and subsequent tubulointerstitutial fibrosis, suggesting that inhibition of ␤ 1 integrin is a possible therapeutic target for prevention of renal fibrosis.

Although early detection and treatment of prostate cancer (PCa) improves outcomes, many patients still die of metastatic PCa. Here, we report that metastatic PCa exhibits reduced levels of the microRNAsmiR-101 and miR-27a. These micro-RNAs (miRNAs) negatively regulate cell invasion and inhibit the expression of FOXM1 and CENPF, two master regulators of metastasis in PCa. Interestingly, the repression of FOXM1 and CENPF by these miRNAs occurs through COUP-TFII, a member of the orphan nuclear receptors family. Loss of miR-101 positively correlates with the increase of COUP-TFII-FOXM1-CENPF activity in clinical PCa data sets, implicating clinical relevance of such regulation. Further studies show that COUP-TFII is a critical factor controlling metastatic gene networks to promote PCa metastasis. Most importantly, this miRNA-COUP-TFII-FOXM1-CENPF regulatory axis is also involved in the development of enzalutaminde resistance. Taken together, our findings highlight the contribution of specific miRNAs through the regulation of the COUP-TFII-FOXM1-CENPF cascade in PCa metastasis and drug resistance.

Hypoxia inducible factor-1 (HIF-1) is the master transcriptional regulator of the cellular response to altered oxygen levels. HIF-1α protein is elevated in most solid tumors and contributes to poor disease outcome by promoting tumor progression, metastasis, and resistance to chemotherapy. To date, the relationship between HIF-1 and these processes, particularly chemoresistance, has remained largely unexplored. Here, we show that expression of the MAPK-specific phosphatase dual-specificity phosphatase-2 (DUSP2) is markedly reduced or completely absent in many human cancers and that its level of expression inversely correlates with that of HIF-1α and with cancer malignancy. Analysis of human cancer cell lines indicated that HIF-1α inhibited DUSP2 transcription, which resulted in prolonged phosphorylation of ERK and, hence, increased chemoresistance. Knockdown of DUSP2 increased drug resistance under normoxia, while forced expression of DUSP2 abolished hypoxia-induced chemoresistance. Further, reexpression of DUSP2 during cancer progression caused tumor regression and markedly increased drug sensitivity in mice xenografted with human tumor cell lines. Furthermore, a variety of genes involved in drug response, angiogenesis, cell survival, and apoptosis were found to be downregulated by DUSP2. Our results demonstrate that DUSP2 is a key downstream regulator of HIF-1-mediated tumor progression and chemoresistance. DUSP2 therefore may represent a novel drug target of particular relevance in tumors resistant to conventional chemotherapy.

Elevated expression of leptin in endometriotic tissue results in an increase in stromal cell proliferation and may contribute to the development of endometriosis. However, the underlying mechanism responsible for aberrant expression of leptin is not known. We hypothesize that aberrant expression of leptin in endometriotic stroma may be regulated by increased levels of hypoxia-inducible factor-1alpha (HIF-1alpha), the master transcription factor that controls gene expression in response to hypoxia. Herein we show that the mRNA and protein levels of HIF-1alpha were greater in ectopic endometriotic tissue compared with its eutopic counterpart. Exposure of eutopic endometrial stromal cells under hypoxic conditions or treated with desferrioxamine (DFO, chemical hypoxia) resulted in a time-dependent increase in leptin gene expression. A promoter activity assay demonstrated that HIF-1alpha induced leptin promoter activity after DFO treatment. Chromatin immunoprecipitation assay further demonstrated that binding of HIF-1alpha to leptin promoter was evident after DFO treatment. Finally, depletion of HIF-1alpha by short interference RNA abolished leptin expression in ectopic endometriotic stromal cells. Taken together, our data demonstrate that aberrant expression of leptin in ectopic endometriotic stromal cells is induced, at least in part, by an elevated level of HIF-1alpha in these cells, providing new insights into the etiology of endometriosis.

The interplay between tumor microenvironment and cancer that causes chemoresistance remains unclear. By analyzing public available microarray datasets, we identified that periostin (POSTN) was overexpressed in cancer stroma in epithelial ovarian cancer (EOC) patients. Immunohistochemistry analysis showed overexpression of stromal POSTN is a powerful independent poor prognostic predictor for EOC patients. Furthermore, patients with high levels of stromal POSTN tend to have higher percentage of cisplatin resistance compared to those with low levels of stromal POSTN. Moreover, we found POSTN treatment can induce cisplatin resistant and activate AKT pathway in A2780 cells in vitro. Inhibition of AKT activity by AKT inhibitor MK-2206 abolished POSTN-induced AKT activation and cisplatin resistance in vitro. Taken together, we found high POSTN expression in cancer microenvironment is correlated with poor prognosis in EOC patients and associated with platinum resistance. The effect of POSTN in cancer stroma cells may activate AKT pathway in tumor and AKT inhibitor can be beneficial to augment the efficacy of existing cancer therapeutics.

No abstract

Our findings provide the novel mechanism that not only functionally links together hypoxic stress, miR20a expression, aberrant ERK phosphorylation, and angiogenesis but also demonstrates that miR20a is an important modulator in the development of endometriosis.