STAT3 imparts BRCAness by impairing homologous recombination repair in Epstein-Barr virus-transformed B lymphocytes

McIntosh, Michael T.; Koganti, Siva; Boatwright, J. Lucas; Li, Xiaofan; Spadaro, Salvatore; Brantly, Alexis C.; Ayers, Jasmine B.; Pérez, Ramón; Burton, Eric; Burgula, Sandeepta; MacCarthy, Thomas; Bhaduri‐McIntosh, Sumita

doi:10.1371/journal.ppat.1008849

Cited by 14 publications

(12 citation statements)

References 57 publications

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“…We also found an association between high levels of pTyr705-Stat3 and BRCA2 mutation, which is more common in ER-positive luminal B tumors ( 39 ). Moreover, consistent with our findings, pTyr705-Stat3 has been reported recently to disrupt CHK1 phosphorylation, thereby impairing BRCA2-mediated RAD51 recruitment for homologous recombination repair of double-strand DNA breaks ( 40 ).…”

Section: Discussionsupporting

confidence: 92%

Stat3 Tyrosine 705 and Serine 727 Phosphorylation Associate With Clinicopathological Characteristics and Distinct Tumor Cell Phenotypes in Triple-Negative Breast Cancer

Stenckova

Nenutil

Vojtěšek

et al. 2022

Pathol. Oncol. Res.

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Signal transducer and activator of transcription 3 (Stat3) is responsible for many aspects of normal development and contributes to the development and progression of cancer through regulating epithelial cell identity and cancer stem cells. In breast cancer, Stat3 is associated with triple-negative breast cancers (TNBC) and its function has been related to the activation of p63, itself a marker of basal-like TNBC and a master regulator of stem cell activities. Stat3 activation is controlled by dual phosphorylation at tyrosine 705 (pTyr705) and serine 727 (pSer727), although it is unclear whether these have equivalent effects, and whether they are related or independent events. To address these issues, we investigated Stat3 phosphorylation at the two sites by immunohistochemistry in 173 patients with TNBC. Stat3 phosphorylation was assessed by automated quantitative measurements of digitized scanned images and classified into four categories based on histoscore. The results were analyzed for associations with multiple markers of tumor phenotype, proliferation, BRCA status, and clinicopathological characteristics. We show that the levels of pTyr705- and pSer727-Stat3 were independent in 34% of tumors. High pTyr705-Stat3 levels were associated with the luminal differentiation markers ERβ/AR and MUC1, whereas tumors with high levels of pSer727-Stat3 were more likely to be positive for the basal marker CK5/6, but were independent of p63 and were EGFR negative. Combined high pSer727- and low Tyr705-Stat3 phosphorylation associated with basal-like cancer. Although high Stat3 phosphorylation levels were associated with less aggressive tumor characteristics, they did not associate with improved survival, indicating that Stat3 phosphorylation is an unfavorable indicator for tumors with an otherwise good prognosis according to clinicopathological characteristics. These findings also show that pTyr705-Stat3 and pSer727-Stat3 associate with specific breast tumor phenotypes, implying that they exert distinct functional activities in breast cancer.

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Section: Discussionsupporting

confidence: 92%

Stat3 Tyrosine 705 and Serine 727 Phosphorylation Associate With Clinicopathological Characteristics and Distinct Tumor Cell Phenotypes in Triple-Negative Breast Cancer

Stenckova

Nenutil

Vojtěšek

et al. 2022

Pathol. Oncol. Res.

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“…More importantly, we further revealed that the downregulation of CFHR3 increased HCC cell growth and metastasis, which was suppressed by the STAT3 inhibitor, S3I-201. As known to us, phosphorylated STAT3 constitutes an essential pathway that regulates the signaling of miscellaneous biological activities including drug resistance, cell metastasis as well as cell proliferation [ 34 , 35 ]. In our study, we confirm that the phosphorylated STAT3 induced by CFHR3 downregulation suppressed p53 expression to promote HCC progression.…”

Section: Discussionmentioning

confidence: 99%

The miR-590-3p/CFHR3/STAT3 signaling pathway promotes cell proliferation and metastasis in hepatocellular carcinoma

Wan

Luo

et al. 2022

Aging

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Accumulating evidence has indicated that Complement factor H-related 3 (CFHR3) plays an essential role in various diseases. However, the biological functions of CFHR3 in hepatocellular carcinoma (HCC) remain largely unclear. Therefore, we perform a further study on CFHR3 in HCC. In this article, we report the suppressive role of CFHR3 in the proliferation and metastasis of HCC cells. CFHR3 downregulation is closely associated with large (T3-T4) HCC, tumor recurrence, and advanced (stage III-IV) clinical stage, functioning as an independent factor for the prognoses of HCC patients. Knockdown of CFHR3 promotes proliferation, migration, and invasion of HCC cells. Mechanistically, downregulation of CFHR3 is induced by miR-590-3p binding to the 3' untranslated region (UTR) of CFHR3. CFHR3 downregulation promotes the phosphorylation of STAT3 protein, thereby suppressing p53 expression. The promotional effect upon downregulation of CFHR3 induced by CFHR3 stable knockdown or miR-590-3p on HCC cell malignant phenotypes is attenuated by STAT3 inhibitor, S3I-201. In conclusion, our results reveal that CFHR3 is a protective biomarker for HCC patients, and targeting the miR-590-3p/CFHR3/p-STAT3/p53 signaling axis provides a promising strategy for HCC therapeutics.

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“…In contrast, histidine triad nucleotide binding protein 1 (HINT1) encodes a protein that hydrolyses purine nucleotide phosphoramidate substrates and is mostly believed to be a tumour suppressor in multiple cancer types [61][62][63]. Another finding in malignant plasma cells is the involvement of genes (MDM2, CCND2, CDK6, STAT3, HLA-F, HLA-B, HLA-C, HLA-E, JUN, PSMC1) in Epstein-Barr virus (EBV) infection and viral carcinogenesis [64][65][66][67]. Further in-depth studies of their roles in EBV infection and plasma cell proliferation are needed in the future.…”

Section: Discussionmentioning

confidence: 99%

Revised International Staging System (R-ISS) stage-dependent analysis uncovers oncogenes and potential immunotherapeutic targets in multiple myeloma

Gong

Yuan

Zhang

et al. 2021

Preprint

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Multiple Myeloma (MM), characterized by high intratumour heterogeneity, accounts for ~10% of all haematologic malignancies. Stratified by the Revised International Staging System (R-ISS), little is known about R-ISS-related plasma cell (PC) heterogeneity, gene expression modules in cytotoxic T/NK cells and immunoregulatory ligands and receptors. Herein, we constructed a single-cell transcriptome atlas of bone marrow in normal and R-ISS-staged MM patients. Focusing on PCs, we identified and validated a subset of GZMA+ cytotoxic PCs. In addition, a malignant PC population with high proliferation capability (proliferating PCs) was associated with unfavourable prognosis and EBV infection in our collected samples. Ribonucleotide Reductase Regulatory Subunit M2 (RRM2), a specific marker of proliferating PCs, was shown to induce MM cell line proliferation and serve as a detrimental marker in MM. Subsequently, three R-ISS-dependent gene modules in cytotoxic CD8+ T and NKT cells were identified and functionally analysed. Finally, cell-cell communication between neutrophils and proliferating PCs with cytotoxic CD8+ T and NKT cells was investigated, which identified intercellular ligand receptors and potential immunotargets such as SIRPA-CD47 and TIGIT-NECTIN3. Collectively, this study provides an R-ISS-related single-cell MM atlas and reveals the clinical significance of two PC clusters, as well as potential immunotargets in MM progression.

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STAT3 imparts BRCAness by impairing homologous recombination repair in Epstein-Barr virus-transformed B lymphocytes

Cited by 14 publications

References 57 publications

Stat3 Tyrosine 705 and Serine 727 Phosphorylation Associate With Clinicopathological Characteristics and Distinct Tumor Cell Phenotypes in Triple-Negative Breast Cancer

Stat3 Tyrosine 705 and Serine 727 Phosphorylation Associate With Clinicopathological Characteristics and Distinct Tumor Cell Phenotypes in Triple-Negative Breast Cancer

The miR-590-3p/CFHR3/STAT3 signaling pathway promotes cell proliferation and metastasis in hepatocellular carcinoma

Revised International Staging System (R-ISS) stage-dependent analysis uncovers oncogenes and potential immunotherapeutic targets in multiple myeloma

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