Protein Tyrosine Phosphatase-N13 Promotes Myofibroblast Resistance to Apoptosis in Idiopathic Pulmonary Fibrosis

Bamberg, Alison; Redente, Elizabeth F.; Groshong, Steve D.; Tuder, Rubin M.; Keith, Rebecca C.; Edelman, Benjamin; Black, Bart P.; Cosgrove, Gregory P.; Wynes, Murry W.; Curran‐Everett, Douglas; Langhe, Stijn De; Ortiz, Luis A.; Thorburn, Andrew; Riches, David W. H.

doi:10.1164/rccm.201707-1497oc

Cited by 25 publications

(24 citation statements)

References 60 publications

(77 reference statements)

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“…It is worth noting that SHP-1 protein encoded by PTPN6 mediates the tumor-suppressive function of TMEFF2 in STAD [37], which indicates expression of PTPN6 might influence the carcinogenesis of STAD patients. PTPN13 has been reported to regulate the resistance of human lung fibroblasts to Fas-induced apoptosis in previous study [38]. Mutated PTPN13 was suggested to be a tumor suppressor gene in colorectal cancer [28].…”

Section: Discussionmentioning

confidence: 90%

The expression patterns and the diagnostic/prognostic roles of PTPN family members in digestive tract cancers

Chen

Yuan

et al. 2020

Cancer Cell Int

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Background: Non-receptor protein tyrosine phosphatases (PTPNs) are a set of enzymes involved in the tyrosyl phosphorylation. The present study intended to clarify the associations between the expression patterns of PTPN family members, and diagnosis as well as the prognosis of digestive tract cancers. Methods: Oncomine and Ualcan were used to analyze PTPN expressions. Data from The Cancer Genome Atlas (TCGA) were downloaded through UCSC Xena for validation and to explore the relationship of the PTPN expression with diagnosis, clinicopathological parameters and survival of digestive tract cancers. Gene ontology enrichment analysis was conducted using the DAVID database. The gene-gene interaction network was performed by GeneMA-NIA and the protein-protein interaction (PPI) network was built using STRING portal coupled with Cytoscape. The expression of differentially expressed PTPNs in cancer cell lines were explored using CCLE. Moreover, by histological verification, the expression of four PTPNs in digestive tract cancers were further analyzed. Results: Most PTPN family members were associated with digestive tract cancers according to Oncomine, Ualcan and TCGA data. Several PTPN members were differentially expressed in digestive tract cancers. For esophageal carcinoma (ESCA), PTPN1 and PTPN12 levels were correlated with incidence; PTPN20 was associated with poor prognosis. For stomach adenocarcinoma (STAD), PTPN2 and PTPN12 levels were correlated with incidence; PTPN3, PTPN5, PTPN7, PTPN11, PTPN13, PTPN14, PTPN18 and PTPN23 were correlated with pathological grade; PTPN20 expression was related with both TNM stage and N stage; PTPN22 was associated with T stage and pathological grade; decreased expression of PTPN5 and PTPN13 implied worse overall survival of STAD, while elevated PTPN6 expression indicated better prognosis. For colorectal cancer (CRC), PTPN2, PTPN21 and PTPN22 levels were correlated with incidence; expression of PTPN5, PTPN12, and PTPN14 was correlated with TNM stage and N stage; high PTPN5 or PTPN7 expression was associated with increased hazards of death. CCLE analyses showed that in esophagus cancer cell lines, PTPN1, PTPN4 and PTPN12 were highly expressed; in gastric cancer cell lines, PTPN2 and PTPN12 were highly expressed; in colorectal cancer cell lines, PTPN12 was highly expressed while PTPN22 was downregulated. Results of histological verification experiment showed differential expressions of PTPN22 in CRC, and PTPN12 in GC and CRC. Conclusions: Members of PTPN family were differentially expressed in digestive tract cancers. Correlations were found between PTPN genes and clinicopathological parameters of patients. Expression of PTPN12 was upregulated

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Section: Discussionmentioning

confidence: 90%

The expression patterns and the diagnostic/prognostic roles of PTPN family members in digestive tract cancers

Chen

Yuan

et al. 2020

Cancer Cell Int

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“…Tyrosine-protein phosphatase nonreceptor type 13 (PTPN13), known as FAP-1 in humans and PTP-BL in mice, negatively regulates FAS-induced apoptosis and NGFR-mediated proapoptotic signaling [15]. PTPN13 promotes pulmonary fibrosis in mice by regulating lung fibroblast resistance to Fas-induced apoptosis [16]. Accumulating evidence suggests that PTPN13 is involved in cancers such as colorectal cancer [17], breast cancer [18], lymphomas [19], and head and neck squamous cell carcinoma [20].…”

Section: Introductionmentioning

confidence: 99%

Anti-oncogene PTPN13 inactivation by hepatitis B virus X protein counteracts IGF2BP1 to promote hepatocellular carcinoma progression

et al. 2020

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Hepatitis B x protein (HBx) affects cellular protein expression and participates in the tumorigenesis and progression of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Metabolic reprogramming contributed to the HCC development, but its role in HBV-related HCC remains largely unclear. Tyrosine-protein phosphatase nonreceptor type 13 (PTPN13) is a significant regulator in tumor development, however, its specific role in hepatocarcinogenesis remains to be explored. Here, we found that decreased PTPN13 expression was associated with HBV/HBx. Patients with low PTPN13 expression showed a poor prognosis. Functional assays revealed that PTPN13 inhibited proliferation and tumorigenesis in vitro and in vivo. Further mechanistic studies indicated that HBx inhibited PTPN13 expression by upregulating the expression of DNMT3A and interacting with DNMT3A. Furthermore, we found that DNMT3A bound to the PTPN13 promoter (−343 to −313 bp) in an epigenetically controlled manner associated with elevated DNA methylation and then inhibited PTPN13 transcription. In addition, we identified IGF2BP1 as a novel PTPN13-interacting gene and demonstrated that PTPN13 influences c-Myc expression by directly and competitively binding to IGF2BP1 to decrease the intracellular concentration of functional IGF2BP1. Overexpressing PTPN13 promoted c-Myc mRNA degradation independent of the protein tyrosine phosphatase (PTP) activity of PTPN13. Importantly, we discovered that the PTPN13-IGF2BP1-c-Myc axis was important for cancer cell growth through promoting metabolic reprogramming. We verified the significant negative correlations between PTPN13 expression and c-Myc, PSPH, and SLC7A1 expression in clinical HCC tissue samples. In summary, our findings demonstrate that PTPN13 is a novel regulator of HBV-related hepatocarcinogenesis and may play an important role in HCC. PTPN13 may serve as a prognostic marker and therapeutic target in HBV-related HCC patients.

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“…Furthermore, our results suggest that impaired Fas signaling e.g. by Fas down-regulation or by increased expression of anti-apoptotic proteins that inhibit pro-apoptotic Fas signaling (10,(16)(17)(18)(19), may lead to critical deviations in lung fibrosis outcome from resolution to persistence.…”

Section: Discussionmentioning

confidence: 82%

“…Fas is expressed by lung fibroblasts and once a pre-defined threshold has been exceeded, Fas ligation induces apoptosis (11,16). In contrast, lung fibroblasts from IPF patients exhibit variable resistance to Fas-induced apoptosis (12,14) due to both down-regulation of Fas expression (16,17) and increased expression of multiple anti-apoptotic genes, including Bcl-2, XIAP, cFLIPL and PTPN13 (10,(18)(19)(20). Together, these in vitro studies have fueled the notion that the acquired resistance of lung fibroblasts to Fasinduced apoptosis promotes pro-fibrotic fibroblast accumulation in the persistently fibrotic lungs of IPF patients (10,14,15,19,21,22).…”

Section: Introductionmentioning

confidence: 99%

Loss of Fas-signaling in pro-fibrotic fibroblasts impairs homeostatic fibrosis resolution and promotes persistent pulmonary fibrosis

Redente

Chakraborty²,

Sajuthi

et al. 2020

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Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic disease of the distal lung alveoli that culminates in respiratory failure and reduced lifespan. Unlike normal lung repair in response to injury, IPF is associated with the accumulation and persistence of fibroblasts and myofibroblasts and continued production of collagen and other extracellular matrix (ECM) components. Prior in vitro studies have led to the hypothesis that the development of resistance to Fas-induced apoptosis by lung fibroblasts and myofibroblasts contibributes to their accumulation in the distal lung tissues of IPF patients. Here, we test this hypothesis in vivo in the resolving model of bleomycin-induced pulmonary fibrosis in mice. Using genetic loss-of-function approaches to inhibit Fas signaling in fibroblasts, novel flow cytometry strategies to quantify lung fibroblast subsets and transcriptional profiling of lung fibroblasts by bulk and single cell RNA-sequencing, we show that Fas is necessary for lung fibroblast apoptosis during homeostatic resolution of bleomycin-induced pulmonary fibrosis in vivo. Furthermore, we show that loss of Fas signaling leads to the persistence and continued pro-fibrotic functions of lung fibroblasts. Our studies provide novel insights into the mechanisms that contribute to fibroblast survival, persistence and continued ECM deposition in the context of IPF and how failure to undergo Fas-induced apoptosis prevents fibrosis resolution.

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Protein Tyrosine Phosphatase-N13 Promotes Myofibroblast Resistance to Apoptosis in Idiopathic Pulmonary Fibrosis

Cited by 25 publications

References 60 publications

The expression patterns and the diagnostic/prognostic roles of PTPN family members in digestive tract cancers

The expression patterns and the diagnostic/prognostic roles of PTPN family members in digestive tract cancers

Anti-oncogene PTPN13 inactivation by hepatitis B virus X protein counteracts IGF2BP1 to promote hepatocellular carcinoma progression

Loss of Fas-signaling in pro-fibrotic fibroblasts impairs homeostatic fibrosis resolution and promotes persistent pulmonary fibrosis

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