TNFRSF19 Inhibits TGFβ Signaling through Interaction with TGFβ Receptor Type I to Promote Tumorigenesis

Deng, Chang‐Mi; Lin, Yu Xin; Qi, Xue; He, Gui; Zhang, Yuchen; Zhang, Hao Jiong; Xu, Miao; Feng, Qi Sheng; Bei, Jin Xin; Zeng, Yi Xin; Feng, Lin

doi:10.1158/0008-5472.can-17-3205

Cited by 39 publications

(28 citation statements)

References 47 publications

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“…Sequence analysis showed that the residues altered by the two mutations are conserved among the members of the TGF‐β receptor family, and thus may be functionally and evolutionarily important . Downregulation of TGF‐β signaling by miR‐93‐targeting TGFBR2 and by TNFRSF19 interaction with TGF‐β receptor I has been reported in NPC to counteract growth inhibition mediated by TGF‐β. In agreement with these previous findings, we showed that these two mutations in TGFBR2 also prevented the growth inhibition.…”

Section: Discussionmentioning

confidence: 99%

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Targeted sequencing of cancer‐related genes in nasopharyngeal carcinoma identifies mutations in the TGF‐β pathway

et al. 2019

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Approximately, 25% of nasopharyngeal carcinoma (NPC) patients develop recurrent disease. NPC may involve relatively few genomic alterations compared to other cancers due to its association with Epstein‐Barr virus (EBV). We envisioned that in‐depth sequencing of tumor tissues might provide new insights into the genetic alterations of this cancer. Thirty‐three NPC paired tumor/adjacent normal or peripheral blood mononuclear cell samples were deep‐sequenced (>1000×) with respect to a panel of 409 cancer‐related genes. Newly identified mutations and its correlation with clinical outcomes were evaluated. Profiling of somatic mutations and copy number variations (CNV) in NPC tumors identified alterations in RTK/RAS/PI3K, NOTCH, DNA repair, chromatin remodeling, cell cycle, NF‐κB, and TGF‐β pathways. In addition, patients harbored CNV among 409 cancer‐related genes and missense mutations in TGF‐β/SMAD signaling were associated with poor overall survival and poor recurrence‐free survival, respectively. The CNV events were correlated with plasma EBV copies, while mutations in TGFBR2 and SMAD4 abrogate SMAD‐dependent TGF‐β signaling. Functional analysis revealed that the new TGFBR2 kinase domain mutants were incapable of transducing the signal, leading to failure of phosphorylation of SMAD2/3 and activation of downstream TGF‐β‐mediated cell growth arrest. This study provides evidence supporting CNV and dysregulated TGF‐β signaling contributes to exacerbating the NPC pathogenesis.

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Section: Discussionmentioning

confidence: 99%

“…Photographs showed the appearance of tumor-bearing nude mice and representative tumor gross. Tumor volumes were measured at day 7,14,21,26,28,32,35,39,42,46, and 48 postinoculation, respectively. Data represented as the mean ± SEM (n = 6) and were analyzed by Student's t test.…”

Section: Discussionmentioning

confidence: 99%

Targeted sequencing of cancer‐related genes in nasopharyngeal carcinoma identifies mutations in the TGF‐β pathway

et al. 2019

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“…3-5). The only inflammation-related genes upregulated by plasminogen were Cxcl9 (an antiangiogenic and anti-fibrotic factor) 24 and Tnfrf19 (an inhibitor of TGF-β signaling) 25 .…”

Section: Plasminogen Treatment Of Radiation-induced Wounds Results Inmentioning

confidence: 99%

Plasminogen is a master regulator and a potential drug candidate for the healing of radiation wounds

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Viklund

Bäckman³

et al. 2020

Cell Death Dis

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Around 95% of cancer patients undergoing radiotherapy experience cutaneous side effects, and some develop radiation wounds or fibrosis. Currently, there is no effective treatment for these indications. We show here that plasminogen administration enhanced the healing of radiation wounds via pleiotropic effects on gene expression. Using RNA sequencing, we found that plasminogen downregulated the expression of genes in the TLR, TNF, WNT, MAPK, and TGF-β signaling pathways, and enhanced the anti-inflammatory effect of arachidonic acid, leading to significantly decreased inflammation and improved remodeling of granulation tissue compared with placebo treatment. In addition, plasminogen induced metabolic changes, including decreased glycolysis. Importantly, many of the factors downregulated by plasminogen are pro-fibrotic. Therefore, in radiation wounds with excessive inflammation, plasminogen is able to enhance and redirect the healing process, such that it more closely resembles physiological healing with significantly reduced risk for developing fibrosis. This makes plasminogen an attractive drug candidate for the treatment of radiation wounds in cancer patients.

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“…We performed OLINK biomarker analysis for a panel of inflammation and cancer-related proteins. This analysis showed that several inflammation-associated factors [CD160 (23), CD27 (24), IL12B (25) and TNFRSF19 (26)] and cancer biomarkers [hK8 (27), Nectin4 (28), KLK13 (29) and CTSV (30)] were correlated with BMI only in breast cancersusceptible individuals, but not in healthy controls (Fig. 1C).…”

Section: Identification Of Plasma Factors From Breast Cancer-susceptimentioning

confidence: 91%

Free Fatty Acids Rewire Cancer Metabolism in Obesity-Associated Breast Cancer via Estrogen Receptor and mTOR Signaling

et al. 2019

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Obesity is a risk factor for postmenopausal estrogen receptor alpha (ERa)-positive (ER þ) breast cancer. Molecular mechanisms underlying factors from plasma that contribute to this risk and how these mechanisms affect ERa signaling have yet to be elucidated. To identify such mechanisms, we performed whole metabolite and protein profiling in plasma samples from women at high risk for breast cancer, which led us to focus on factors that were differentially present in plasma of obese versus nonobese postmenopausal women. These studies, combined with in vitro assays, identified free fatty acids (FFA) as circulating plasma factors that correlated with increased proliferation and aggressiveness in ER þ breast cancer cells. FFAs activated both the ERa and mTOR pathways and rewired metabolism in breast cancer cells. Pathway preferential estrogen-1 (PaPE-1), which targets ERa and mTOR sig-naling, was able to block changes induced by FFA and was more effective in the presence of FFA. Collectively, these data suggest a role for obesity-associated gene and metabolic rewiring in providing new targetable vulnerabilities for ER þ breast cancer in postmenopausal women. Furthermore, they provide a basis for preclinical and clinical trials where the impact of agents that target ERa and mTOR signaling cross-talk would be tested to prevent ER þ breast cancers in obese postmenopausal women. Significance: These findings show that obesity-associated changes in certain blood metabolites rewire metabolic programs in cancer cells, influence mammary epithelial cell tumorigenicity and aggressiveness, and increase breast cancer risk.

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TNFRSF19 Inhibits TGFβ Signaling through Interaction with TGFβ Receptor Type I to Promote Tumorigenesis

Cited by 39 publications

References 47 publications

Targeted sequencing of cancer‐related genes in nasopharyngeal carcinoma identifies mutations in the TGF‐β pathway

Targeted sequencing of cancer‐related genes in nasopharyngeal carcinoma identifies mutations in the TGF‐β pathway

Plasminogen is a master regulator and a potential drug candidate for the healing of radiation wounds

Free Fatty Acids Rewire Cancer Metabolism in Obesity-Associated Breast Cancer via Estrogen Receptor and mTOR Signaling

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