Angiotensin-converting enzyme 2 attenuates the metastasis of non-small cell lung cancer through inhibition of epithelial-mesenchymal transition

Qian, Yanrong; Guo, Yi; Wan, Huanying; Fan, Lei; Feng, Yun; Ni, Lei; Xiang, Yi; Li, Qingyun

doi:10.3892/or.2013.2370

Cited by 63 publications

(57 citation statements)

References 28 publications

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“…Thus, it is likely that down‐regulation of TGF‐β1 in 9‐month‐old Mdr2‐KO mice might favor cancer growth and that up‐regulation of TGF‐β1 expression by ACE2 therapy could oppose this. Indeed, we found that a majority of Mdr2‐KO mice at 9 months of age had developed liver tumor nodules that were absent in ACE2‐treated mice (data not shown), supporting the work showing inhibition of lung cancer metastasis by ACE2 . In further support of this argument, ACE2 therapy restored the loss of e‐cadherin in cholangiocytes and/or hepatocytes, and the loss of e‐cadherin is strongly linked to the development of sclerosing cholangitis, peribiliary fibrosis, EMT, and hepatocellular carcinoma .…”

Section: Discussionsupporting

confidence: 81%

“…Indeed, we found that a majority of Mdr2-KO mice at 9 months of age had developed liver tumor nodules that were absent in ACE2-treated mice (data not shown), supporting the work showing inhibition of lung cancer metastasis by ACE2. (35) In further support of this argument, ACE2 therapy restored the loss of e-cadherin in cholangiocytes and/or hepatocytes, and the loss of e-cadherin is strongly linked to the development of sclerosing cholangitis, peribiliary fibrosis, EMT, and hepatocellular carcinoma. (18,35) However, inhibitory effects of ACE2 on tumor growth are not discussed in this report as it is beyond the scope of the present study.…”

Section: Discussionmentioning

confidence: 88%

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Liver‐Targeted Angiotensin Converting Enzyme 2 Therapy Inhibits Chronic Biliary Fibrosis in Multiple Drug‐Resistant Gene 2‐Knockout Mice

Rajapaksha¹,

Gunarathne²,

Asadi

et al. 2019

Hepatol Commun

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There is a large unmet need for effective therapies for cholestatic disorders, including primary sclerosing cholangitis (PSC), a disease that commonly results in liver failure. Angiotensin (Ang) II of the renin Ang system (RAS) is a potent profibrotic peptide, and Ang converting enzyme 2 (ACE2) of the alternate RAS breaks down Ang II to antifibrotic peptide Ang‐(1‐7). In the present study, we investigated long‐term effects of ACE2 delivered by an adeno‐associated viral vector and short‐term effects of Ang‐(1‐7) peptide in multiple drug‐resistant gene 2‐knockout (Mdr2‐KO) mice. These mice develop progressive biliary fibrosis with pathologic features closely resembling those observed in PSC. A single intraperitoneal injection of ACE2 therapy markedly reduced liver injury (P < 0.05) and biliary fibrosis (P < 0.01) at both established (3‐6 months of age) and advanced (7‐9 months of age) disease compared to control vector‐injected Mdr2‐KO mice. This was accompanied by increased hepatic Ang‐(1‐7) levels (P < 0.05) with concomitant reduction in hepatic Ang II levels (P < 0.05) compared to controls. Moreover, Ang‐(1‐7) peptide infusion improved liver injury (P < 0.05) and biliary fibrosis (P < 0.0001) compared to saline‐infused disease controls. The therapeutic effects of both ACE2 therapy and Ang‐(1‐7) infusion were associated with significant (P < 0.01) reduction in hepatic stellate cell (HSC) activation and collagen expression. While ACE2 therapy prevented the loss of epithelial characteristics of hepatocytes and/or cholangiocytes in vivo, Ang‐(1‐7) prevented transdifferentiation of human cholangiocytes (H69 cells) into the collagen‐secreting myofibroblastic phenotype in vitro. We showed that an increased ratio of hepatic Ang‐(1‐7) to Ang II levels by ACE2 therapy results in the inhibition of HSC activation and biliary fibrosis. Conclusion: ACE2 therapy has the potential to treat patients with biliary diseases, such as PSC.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 88%

Liver‐Targeted Angiotensin Converting Enzyme 2 Therapy Inhibits Chronic Biliary Fibrosis in Multiple Drug‐Resistant Gene 2‐Knockout Mice

Rajapaksha¹,

Gunarathne²,

Asadi

et al. 2019

Hepatol Commun

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“…ACE2 activation has been shown to have beneficial effects in a variety of disease states [52]. Furthermore, Ang 1-7 has been shown to be beneficial in the setting of systemic hypertension [53,54], pulmonary hypertension [55], renal disease [56] and cancer [57][58][59]. Since ACE2 has been found in the brain [60,61] it seems reasonable that this enzyme and its product, Ang 1-7, would modulate the generation of central sympathetic outflow in CHF.…”

Section: A Role For Angiotensin Converting Enzyme (Ace) 2 In the Sympmentioning

confidence: 99%

The central renin–angiotensin system and sympathetic nerve activity in chronic heart failure

2014

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Chronic heart failure (CHF) is a multi-factorial disease process that is characterized by over activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system. Both of these systems are chronically activated in CHF. The RAAS consists of an excitatory arm involving Angiotensin II (Ang II), Angiotensin Converting Enzyme (ACE), and the Ang II type 1 Receptor (AT1R). The RAAS also consists of a protective arm consisting of Angiotensin-1-7 (Ang -1-7), the Ang II type 2 receptor (AT2R), ACE2 and the mas receptor. Sympathoexcitation in CHF is driven, in large part, by an imbalance of these two arms, with an increase in the Ang II-AT1R-ACE arm and a decrease in the AT2R-ACE2 arm. This imbalance is manifested in cardiovascular-control regions of the brain such as the rostral ventrolateral medulla and paraventricular nucleus in the hypothalamus. This review focuses on current literature that describes the components of these two arms of the RAAS, and their imbalance in the CHF state. Moreover, this review provides additional evidence for the relevance of ACE2 and Ang-1-7 as key players in the regulation of central sympathetic outflow in CHF. Finally we also examine the effects of exercise training as a therapeutic strategy and the molecular mechanisms at play in CHF, in part, because of the ability of exercise training to restore the balance of the RAAS axis and sympathetic outflow.

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“…Qian et al (2013) reported that ACE2 up-regulates the expression of E-cadherin both in vitro and in vivo and that it down-regulates vimentin, which are both representative markers of the EMT. Furthermore, a western blot analysis indicated that ACE2 attenuates the TGF-β1-mediated EMT of A549 cells.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, a western blot analysis indicated that ACE2 attenuates the TGF-β1-mediated EMT of A549 cells. ACE2 has been found to decrease the transcriptional levels of genes associated with the EMT in vitro , and exposing cells to DX600, an inhibitor of ACE2, recovers the sensitivity of lung cancer cells to TGF-β1 (Qian et al, 2013). These data suggest that ACE2 attenuates lung cancer metastasis by inhibiting the EMT, and they further indicate that ACE2 may represent a potential therapeutic target in treating lung cancer, where the EMT contributes to the development of tumor metastasis.…”

Section: Introductionmentioning

confidence: 99%

The ACE2/Angiotensin-(1–7)/Mas Receptor Axis: Pleiotropic Roles in Cancer

Fan

et al. 2017

Front. Physiol.

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Cancer remains one of the most common causes of death and disability and represents a major economic burden in industrialized nations. The renin-angiotensin system (RAS) has been well-recognized as one of the most important regulators of both normal and pathological physiological processes in the brain, kidney, heart, and blood vessels. The activation of the angiotensin-converting enzyme 2/angiotensin-(1–7)/mitochondrial assembly receptor [ACE2/Ang-(1–7)/MasR] axis, which is one component of the RAS, has recently been identified as a critical component of pulmonary systems, gastric mucosa, and cancer. However, the ability of the ACE2/Ang-(1–7)/MasR axis to suppress or promote cancer has not been fully elucidated. In this review, we focus on recent experimental and clinical studies investigating the basic properties, roles, and mechanisms of ACE2, Ang-(1–7), and the MasR, as well as the axis pathway, to provide insights into possible therapeutic strategies for treating cancer that target the ACE2/Ang-(1–7)/MasR axis.

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Angiotensin-converting enzyme 2 attenuates the metastasis of non-small cell lung cancer through inhibition of epithelial-mesenchymal transition

Cited by 63 publications

References 28 publications

Liver‐Targeted Angiotensin Converting Enzyme 2 Therapy Inhibits Chronic Biliary Fibrosis in Multiple Drug‐Resistant Gene 2‐Knockout Mice

Liver‐Targeted Angiotensin Converting Enzyme 2 Therapy Inhibits Chronic Biliary Fibrosis in Multiple Drug‐Resistant Gene 2‐Knockout Mice

The central renin–angiotensin system and sympathetic nerve activity in chronic heart failure

The ACE2/Angiotensin-(1–7)/Mas Receptor Axis: Pleiotropic Roles in Cancer

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