Cyclophilin A Function in Mammary Epithelium Impacts Jak2/Stat5 Signaling, Morphogenesis, Differentiation, and Tumorigenesis in the Mammary Gland

Volker, Sonja E.; Hedrick, Shannon E.; Feeney, Yvonne B.; Clevenger, Charles V.

doi:10.1158/0008-5472.can-17-2892

Cited by 17 publications

(17 citation statements)

References 52 publications

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“…Peptidylprolyl isomerase A as one of the most abundant members of cyclophilin (Cyp) family proteins has been reported upregulated in breast cancer ( Volker et al, 2018 ), esophageal cancer ( Qi et al, 2008 ), small cell lung cancer ( Campa et al, 2003 ), colorectal cancer ( Wong et al, 2008 ), pancreatic cancer ( Li et al, 2013 ), melanoma ( Caputo et al, 2011 ), malignant glioblastoma ( Sun et al, 2011 ; Saw et al, 2018 ), serous ovarian cancer ( Qi et al, 2019 ), and skin cancer ( Han et al, 2012 ). Cyps possess a peptidyl prolyl isomerase (PPIase), catalyzing the conversion between cis-trans isomers of proline on the peptide ( Lee, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

A Critical Role of Peptidylprolyl Isomerase A Pseudogene 22/microRNA-197-3p/Peptidylprolyl Isomerase A Axis in Hepatocellular Carcinoma

Wang

Chen

et al. 2021

Front. Genet.

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The burden of hepatocellular carcinoma (HCC) worldwide is increasing over time, while the underlying molecular mechanism of HCC development is still under exploration. Pseudogenes are classified as a special type of long non-coding RNAs (lncRNAs), and they played a vital role in regulating tumor-associated gene expression. Here, we report that a pseudogene peptidylprolyl isomerase A pseudogene 22 (PPIAP22) and its parental gene peptidylprolyl isomerase A (PPIA) were upregulated in HCC and were associated with the clinical outcomes of HCC. Further investigation revealed that PPIAP22 might upregulate the expression of PPIA through sponging microRNA (miR)-197-3p, behaving as competing endogenous RNA (ceRNA). PPIA could participate in the development of HCC by regulating mRNA metabolic process and tumor immunity based on the functional enrichment analysis. We also found a strong correlation between the expression levels of PPIA and the immune cell infiltration or the expression of chemokines, especially macrophage, C-C motif chemokine ligand 15 (CCL15), and C-X-C motif chemokine ligand 12 (CXCL12). Our findings demonstrate that the PPIAP22/miR-197-3p/PPIA axis plays a vital role in the progression of HCC by increasing the malignancy of tumor cells and regulating the immune cell infiltration, especially macrophage, through CCL15-CCR1 or CXCL12-CXCR4/CXCR7 pathways.

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Section: Discussionmentioning

confidence: 99%

A Critical Role of Peptidylprolyl Isomerase A Pseudogene 22/microRNA-197-3p/Peptidylprolyl Isomerase A Axis in Hepatocellular Carcinoma

Wang

Chen

et al. 2021

Front. Genet.

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“…Regarding tumor development, Volker et al (Volker et al, 2018) showed that Cyps promote mammary tumorigenesis in mice. In a non-small cell lung cancer murine model, overexpression of Cyps elevated tumor metastasis rate compared to those with downregulated Cyps (Guo et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Cyclophilin Inhibitor NV556 Reduces Fibrosis and Hepatocellular Carcinoma Development in Mice With Non-Alcoholic Steatohepatitis

et al. 2019

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Hepatocellular carcinoma (HCC), the third major cause of cancer mortality, can result from non-alcoholic steatohepatitis (NASH). Due to limited efficacy of drugs approved for HCC and no drug available yet for NASH, identification of new effective treatments is crucial. Here, we investigated whether NV556, a cyclophilin inhibitor derived from sanglifehrins, would decrease the development of NASH and HCC in a preclinical mouse model. For our experiment, male mice were administered streptozotocin to disrupt pancreatic cells and nourished with high-fat diet since 3 weeks of age. Afterward, NV556 or vehicle was orally administered daily for 6 weeks before the 14-week-old time point for the development of NASH, or 10 weeks before the 30-week-old time point for the establishment of HCC. Body weight, blood glucose level, and liver weight were recorded. Moreover, for NASH, livers were histologically examined for inflammation and steatosis. Collagen was measured by Sirius Red staining of hepatic tissues. Systemic cytokine levels in serum were detected by multiplex assays. For HCC, nodules of livers were measured and scored according to a developed system with number and size of nodules as criteria. NV556 significantly decreased collagen deposition (p = 0.0281), but did not alter inflammation, steatosis, body and liver weight, and systemic cytokine production compared to control mice with NASH symptoms. For HCC, NV556 statistically reduced the number (p = 0.0091) and diameter of tumorous nodules (p = 0.0264), along with liver weight (p = 0.0026) of mice.Our study suggests NV556 as a promising candidate for treatment of NASH-derived fibrosis and HCC.

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“…This would argue that NIM811 affects metastatic outgrowth, but does not alter micro-metastatic seeding, and further studies are planned to examine the mechanistic basis for this effect. Significant alterations in mammary cancer progression were also observed in the PyMT spontaneous model ( Volker et al., 2018 ). CypA −/- × PyMT mice demonstrated a highly significant decrease in tumor burden in comparison with the CypA +/+ × PyMT cohorts ( Figure 7 ).…”

Section: Discussionmentioning

confidence: 93%

Inhibition of the Activity of Cyclophilin A Impedes Prolactin Receptor-Mediated Signaling, Mammary Tumorigenesis, and Metastases

Hakim¹,

Craig²,

Koblinski³

et al. 2020

iScience

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Summary Prolactin (PRL) and its receptor (PRLr) play important roles in the pathogenesis of breast cancer. Cyclophilin A (CypA) is a cis-trans peptidyl-prolyl isomerase (PPI) that is constitutively associated with the PRLr and facilitates the activation of the tyrosine kinase Jak2. Treatment with the non-immunosuppressive prolyl isomerase inhibitor NIM811 or CypA short hairpin RNA inhibited PRL-stimulated signaling, breast cancer cell growth, and migration. Transcriptomic analysis revealed that NIM811 inhibited two-thirds of the top 50 PRL-induced genes and a reduction in gene pathways associated with cancer cell signaling. In vivo treatment of NIM811 in a TNBC xenograft lessened primary tumor growth and induced central tumor necrosis. Deletion of CypA in the MMTV-PyMT mouse model demonstrated inhibition of tumorigenesis with significant reduction in lung and lymph node metastasis. The regulation of PRLr/Jak2-mediated biology by NIM811 demonstrates that a non-immunosuppressive prolyl isomerase inhibitor can function as a potential breast cancer therapeutic.

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Cyclophilin A Function in Mammary Epithelium Impacts Jak2/Stat5 Signaling, Morphogenesis, Differentiation, and Tumorigenesis in the Mammary Gland

Cited by 17 publications

References 52 publications

A Critical Role of Peptidylprolyl Isomerase A Pseudogene 22/microRNA-197-3p/Peptidylprolyl Isomerase A Axis in Hepatocellular Carcinoma

A Critical Role of Peptidylprolyl Isomerase A Pseudogene 22/microRNA-197-3p/Peptidylprolyl Isomerase A Axis in Hepatocellular Carcinoma

Cyclophilin Inhibitor NV556 Reduces Fibrosis and Hepatocellular Carcinoma Development in Mice With Non-Alcoholic Steatohepatitis

Inhibition of the Activity of Cyclophilin A Impedes Prolactin Receptor-Mediated Signaling, Mammary Tumorigenesis, and Metastases

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