Pan-cancer analyses of classical protein tyrosine phosphatases and phosphatase-targeted therapy in cancer

Wang, Tao; Ba, Xinlei; Zhang, Xiaonan; Zhang, Na; Wang, Guowen; Bai, Bin; Li, Tong; Zhao, Jiahui; Zhao, Yuemin; Yu, Yang; Wang, Bing

doi:10.3389/fimmu.2022.976996

Cited by 3 publications

(3 citation statements)

References 65 publications

(66 reference statements)

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“…Gene expressing matrix and area under the dosage response curve of glioma cell lines were collected from the GDSC database [ 35 , 36 ]. Correlation coefficient |Rs| > 0.25 and FDR < 0.05 were employed to further analysis [ 37 ]. In addition, previously conducted studies were used to obtain imputed tumor response data for 138 anti-cancer drugs, which were subsequently used to assess treatment response for GBM patients [ 38 ].…”

Section: Methodsmentioning

confidence: 99%

Single-cell and bulk sequencing analyses reveal the immune suppressive role of PTPN6 in glioblastoma

Zhang,

Chen,

Zhang

et al. 2023

Aging

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Glioblastoma (GBM) is a highly malignant brain cancer with a poor prognosis despite standard treatments. This investigation aimed to explore the feasibility of PTPN6 to combat GBM with immunotherapy. Our study employed a comprehensive analysis of publicly available datasets and functional experiments to assess PTPN6 gene expression, prognostic value, and related immune characteristics in glioma. We evaluated the influence of PTPN6 expression on CD8+ T cell exhaustion, immune suppression, and tumor growth in human GBM samples and mouse models. Our findings demonstrated that PTPN6 overexpression played an oncogenic role in GBM and was associated with advanced tumor grades and unfavorable clinical outcomes. In human GBM samples, PTPN6 upregulation showed a strong association with immunosuppressive formation and CD8+ T cell dysfunction, whereas, in mice, it hindered CD8+ T cell infiltration. Moreover, PTPN6 facilitated cell cycle progression, inhibited apoptosis, and promoted glioma cell proliferation, tumor growth, and colony formation in mice. The outcomes of our study indicate that PTPN6 is a promising immunotherapeutic target for the treatment of GBM. Inhibition of PTPN6 could enhance CD8+ T cell infiltration and improve antitumor immune response, thus leading to better clinical outcomes for GBM patients.

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Section: Methodsmentioning

confidence: 99%

Single-cell and bulk sequencing analyses reveal the immune suppressive role of PTPN6 in glioblastoma

Zhang,

Chen,

Zhang

et al. 2023

Aging

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“…A study also demonstrated that PTPN18 promotes endometrial cancer cell line proliferation and metastasis but inhibits their apoptosis [11]. We previously performed the pan-cancer analysis of classical protein tyrosine phosphatases [12] and confirmed that PTPN18 can inhibit breast cancer metastasis [13]. However, the potential functions and mechanisms of PTPN18 in glioblastoma remain unclear.…”

Section: Introductionmentioning

confidence: 92%

PTPN18 Serves as a Potential Oncogene for Glioblastoma by Enhancing Immune Suppression

Wang

et al. 2023

Oxidative Medicine and Cellular Longevity

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Glioblastoma is characterized as one of the deadliest cancers in humans. The survival time is not improved by standard treatment. Although immunotherapy has revolutionized cancer treatment, the current therapy targets for glioblastoma patients are not satisfied. We systematically analyzed the expression patterns, predictive values, and immunological characteristics of PTPN18 in glioblastoma. The independent datasets and functional experiments were employed to validate our findings. Our data showed that PTPN18 is potentially cancerogenic in glioblastoma with advanced grades and poor prognosis. High expression of PTPN18 correlated with CD8+ T cell exhaustion and immune suppression in glioblastoma. In addition, PTPN18 facilitates glioblastoma progression by accelerating glioma cell prefiltration, colony formation, and tumor growth in mice. PTPN18 also promotes cell cycle progression and inhibits apoptosis. Our results illustrate the characterization of PTPN18 in glioblastoma and highlight the potential value as an immunotherapeutic target for glioblastoma treatment.

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“…Together, kinases and PTPs guard a balance in innumerable cell signaling pathways. Loss of this balance has been linked to a plethora of human diseases, including cancer (Hendriks et al, 2013;Tautz et al, 2013;Tonks, 2006; T. Wang et al, 2022).…”

Section: Table Of Contentsmentioning

confidence: 99%

Protein tyrosine phosphatases in zebrafish development and regeneration

Allers

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Protein tyrosine phosphatases (PTPs) have a central role in cell signaling, by dephosphorylating other proteins. PTPs are highly susceptible to oxidation, due to the low pKa of their active sites. Their reactive cysteine gets oxidized, which leads to the temporary inactivation of the PTP. It has been shown in many different species that a burst of Reactive Oxygen Species (ROS) is produced upon injury. This burst of ROS plays an important role in wound healing and regeneration. We hypothesized that the ROS could start a signaling cascade by oxidizing PTPs. Previously, eight PTPs were identified that were specifically oxidized in response to amputation of the tail fin of adult zebrafish. One of these PTPs, Shp2a, was shown to be essential for regeneration. In chapter 2 we describe how we generated zebrafish knockouts of 6 PTPs that were shown previously to be oxidized upon amputation of the caudal fin and their paralogs. We show that these PTPs were not essential for regeneration. In addition, we did not recapitulate all the phenotypes we expected. We hypothesize that this is due to genetic compensation. In chapter 3 we describe our investigation of zebrafish with a knockout of ptpn4a. We show that the majority of the mutant zebrafish died at the juvenile stage and suffered from epileptic seizures. This corresponds to human patients who suffer from intellectual disability and epileptic seizures due to nonsense mutations in PTPN4. We show that a minority of the mutant zebrafish compensated for the loss of Ptpn4a and survived, but also that a separate knockout line lost its compensation ability over time and showed enhanced lethality at the juvenile stage. In chapter 4 we describe our investigation of zebrafish with a knockout of ptpn6. We show that these mutant zebrafish displayed fully penetrant mortality at the larval stage and died from lethal hyperinflammation. This corresponds to the phenotype of the motheaten mice lacking SHP1 and human patients suffering from neutrophilic dermatoses and emphysema. We show that loss of Shp1 led to a reduced number of emerging HSPCs, increased HSPC proliferation, an increased number of macrophages and a decreased number of neutrophils. In addition, we show that loss of Shp1 affected the behavior of neutrophils and macrophages and led to reduced directional migration upon wounding. In chapter 5 we describe how we investigated the role of oxidation of Shp2a during regeneration, by creating a fusion protein consisting of Shp2a linked with Catalase. Due to the close vicinity, the Catalase protected Shp2a from oxidation. We show that by inhibiting oxidation of Shp2a, we inhibited regeneration. This indicates that transient oxidation of Shp2a is an essential step in the signaling cascade that results in regeneration. This research puts an end to the apparent paradox that Shp2a is oxidized during regeneration, but that catalytic activity of Shp2a is essential for regeneration to proceed. We hypothesize that transient oxidation of Shp2a leads to a reduction of a negative feedback loop, resulting in increased signaling activity once Shp2a is reduced again.

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Pan-cancer analyses of classical protein tyrosine phosphatases and phosphatase-targeted therapy in cancer

Cited by 3 publications

References 65 publications

Single-cell and bulk sequencing analyses reveal the immune suppressive role of PTPN6 in glioblastoma

Single-cell and bulk sequencing analyses reveal the immune suppressive role of PTPN6 in glioblastoma

PTPN18 Serves as a Potential Oncogene for Glioblastoma by Enhancing Immune Suppression

Protein tyrosine phosphatases in zebrafish development and regeneration

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