Hypoxia-inducible Factor 1 Mediates Nasal Polypogenesis by Inducing Epithelial-to-Mesenchymal Transition

Abstract Hyperglycemia-induced renal epithelial-to-mesenchymal transition (EMT) is a key pathological factor in diabetic renal tubulointerstitial fibrosis (RIF). Our previous studies have shown that connexin 43 (Cx43) activation attenuated the development of diabetic renal fibrosis. However, whether Cx43 regulates the EMT of renal tubular epithelial cells (TECs) and the pathological process of RIF under the diabetic conditions remains to be elucidated. In the present study, we identified that Cx43 protein expression was down-regulated in the kidney tissues of db/db mice as well as in high glucose (HG)-induced NRK-52E cells. Overexpression of Cx43 improved renal function in db/db spontaneous diabetic model mice, increased SIRT1 levels, decreased hypoxia-inducible factor (HIF)-1α expression, and reduced production of EMT markers and extracellular matrix (ECM) components. Additionally, Cx43 overexpression inhibited the EMT process and reduced the expression of ECM components such as fibronectin (FN), Collagen I, and Collagen IV in HG-induced NRK-52E cells, whereas Cx43 deficiency had the opposite effects. Mechanistically, Cx43 in a carboxyl-terminal signal transduction-dependent manner could up-regulate SIRT1 expression and enhance SIRT1-dependent deacetylation of HIF-1α to reduce HIF-1α activity, which eventually ameliorated renal EMT and diabetic RIF. Our study indicates the essential role of Cx43 in regulating renal EMT and diabetic RIF via regulating the SIRT1-HIF-1α signaling pathway and provides an experimental basis for Cx43 as a potential target for diabetic nephropathy (DN).

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ATP Synthase Subunit Epsilon Overexpression Promotes Metastasis by Modulating AMPK Signaling to Induce Epithelial-to-Mesenchymal Transition and Is a Poor Prognostic Marker in Colorectal Cancer Patients

Journal of Clinical Medicine ◽

10.3390/jcm8071070 ◽

2019 ◽

Vol 8 (7) ◽

pp. 1070 ◽

Cited By ~ 4

Author(s):

Yan-Jiun Huang ◽

Yi-Hua Jan ◽

Yu-Chan Chang ◽

Hsing-Fang Tsai ◽

Alexander TH Wu ◽

...

Keyword(s):

Colon Cancer ◽

Atp Synthase ◽

Distant Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Hypoxia Inducible Factor ◽

Xenograft Model ◽

Metastatic Colon Cancer ◽

Mesenchymal Transition ◽

Ampk Signaling ◽

Mouse Xenograft Model

Metastasis remains the major cause of death from colon cancer. We intend to identify differentially expressed genes that are associated with the metastatic process and prognosis in colon cancer. ATP synthase epsilon subunit (ATP5E) gene was found to encode the mitochondrial F0F1 ATP synthase subunit epsilon that was overexpressed in tumor cells compared to their normal counterparts, while other genes encoding the ATP synthase subunit were repressed in public microarray datasets. CRC cells in which ATP5E was silenced showed markedly reduced invasive and migratory abilities. ATP5E inhibition significantly reduced the incidence of distant metastasis in a mouse xenograft model. Mechanistically, increased ATP5E expression resulted in a prominent reduction in E-cadherin and an increase in Snail expression. Our data also showed that an elevated ATP5E level in metastatic colon cancer samples was significantly associated with the AMPK-AKT-hypoxia-inducible factor-1α (HIF1α) signaling axis; silencing ATP5E led to the degradation of HIF1α under hypoxia through AMPK-AKT signaling. Our findings suggest that elevated ATP5E expression could serve as a marker of distant metastasis and a poor prognosis in colon cancer, and ATP5E functions via modulating AMPK-AKT-HIF1α signaling.

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Curcumin Suppresses Hepatic Stellate Cell-Induced Hepatocarcinoma Angiogenesis and Invasion through Downregulating CTGF

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/8148510 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 11

Author(s):

Shan Shao ◽

Wanxing Duan ◽

Qinhong Xu ◽

Xuqi Li ◽

Liang Han ◽

...

Keyword(s):

Growth Factor ◽

Epithelial To Mesenchymal Transition ◽

Stellate Cell ◽

Hypoxia Inducible Factor ◽

Vascular Endothelial Cell ◽

Vital Role ◽

Tissue Growth ◽

Related Factor ◽

Ros Scavenging ◽

Mesenchymal Transition

Microenvironment plays a vital role in tumor progression; we focused on elucidating the role of hepatic stellate cells (HSCs) in hepatocarcinoma (HCC) aggressiveness and investigated the potential protective effect of curcumin on HSC-driven hepatocarcinoma angiogenesis and invasion. Our data suggest that HSCs increase HCC reactive oxygen species (ROS) production to upregulate hypoxia-inducible factor-1α (HIF-1α) expression to promote angiogenesis, epithelial to mesenchymal transition (EMT) process and invasion. And HSCs could secrete soluble factors, such as interleukin-6 (IL-6), vascular endothelial cell growth factor (VEGF), and stromal-derived factor-1 (SDF-1) to facilitate HCC progression. Curcumin could significantly suppress the above HSC-induced effects in HCC and could abrogate ROS and HIF-1α expression in HCC. HIF-1α or connective tissue growth factor (CTGF) knockdown could abolish the aforementioned curcumin affection. Moreover, CTGF is a downstream gene of HIF-1α. In addition, nuclear factor E2-related factor 2 (Nrf2) and glutathione (GSH) are involved in curcumin protection of HCC. These data indicate that curcumin may induce ROS scavenging by upregulating Nrf2 and GSH, thus inhibiting HIF-1α stabilization to suppress CTGF expression to exhibit its protection on HCC. Curcumin has a promising therapeutic effect on HCC. CTGF is responsible for curcumin-induced protection in HCC.

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Significance of hypoxia inducible factor-1 expression in liver metastasis of colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.464 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 464-464

Author(s):

Yuma Wada ◽

Yuji Morine ◽

Satoru Imura ◽

Tetsuya Ikemoto ◽

Shuichi Iwahashi ◽

...

Keyword(s):

Liver Metastasis ◽

Hypoxia Inducible Factor ◽

Metastatic Lesion ◽

Primary Lesion ◽

Clinicopathological Factors ◽

Negative Group ◽

Mesenchymal Transition ◽

Positive Group ◽

Hypoxia Inducible Factor 1 ◽

The Difference

464 Background: In colorectal liver metastasis (CRLM), the difference of tumor malignancy between primary and metastatic lesion has been elucidated. Hypoxia inducible factor-1 (HIF-1) represent tumor malignancy including angiogenesis, tumor growth and epithelial mesenchymal transition (EMT). The aim of this study was to investigate the difference of tumor malignancy between metastatic and primary lesion of CRLM and its impact for patient’s prognosis. Methods: In an initial curative hepatectomy of 75 cases in CRLM, HIF-1 expression in primary and metastatic lesion was evaluated by immunostaining method (Sigma-Aldrich, HPA 001275). Staining score was classified as follows, staining intensity (0: negative, 1: low, 2: medium, 3: high) and staining area (0: 0%, 1: -25%, 2: 26-50%, 3: ≥ 51%), and defined more than 4 points as positive expression. We evaluated the clinicopathological features according to HIF-1 expression. Results: Regarding HIF-1 expression of metastatic site, we divided into the positive group (n = 54) and the negative group (n = 21). There was no difference between metastatic HIF-1 expression and clinicopathological factors. Nevertheless, in overall survival, multivariate analysis revealed that HIF-1 positive in metastasis (HR: 2.850, p = 0.042) and poor differentiation type of primary lesion (HR: 20.873, p = 0.001) were independent prognostic factors. HIF-1 positive and negative patients were 3 year survival of 95.2% and 58.6%, respectively. Also, in disease free survival, HIF-1 positive in metastasis (HR: 2.608, p = 0.004), Synchronous (HR: 1.794, p = 0.049), Grade BC (HR: 2.145, p = 0.008), and lymph node metastasis in primary lesion (HR: 2.070, p = 0.016) was identified. Regarding HIF-1 expression of primary site, we divided into 51 cases of positive group and 24 cases of negative group. There was no relationship to clinicopathological factors as well as HIF-1 expression in metastasis, besides HIF-1 expression of prognosis was not associated. Conclusions: In CRLM, HIF-1 expression in the metastatic lesion is not associated with the primary lesion and may be useful as prognostic marker.

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