Targeting STAT3 and STAT5 in Cancer

Araujo, Elvin D. de; Keserü, György M.; Gunning, Patrick T.; Moriggl, Richard

doi:10.3390/cancers12082002

Cited by 8 publications

(9 citation statements)

References 56 publications

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“…Numerous reports have shown that gain‐of‐function (GOF) mutations (i.e., somatic or acquired variations) in STAT proteins are a basis for oncogenesis in neoplastic cells. 7 , 8 , 9 , 10 , 11 …”

Section: Introductionmentioning

confidence: 99%

“…Depending on the biological processes involved, the presence of cytokines, and underlying conditions and pathologies, they have a unique STAT interactome that illuminates the pleiotropic action of STAT family members. Numerous reports have shown that gain‐of‐function (GOF) mutations (i.e., somatic or acquired variations) in STAT proteins are a basis for oncogenesis in neoplastic cells 7–11 …”

Section: Introductionmentioning

confidence: 99%

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JAK‐STAT core cancer pathway: An integrative cancer interactome analysis

Erdogan

Radu

Orlova

et al. 2022

J Cellular Molecular Medi

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Through a comprehensive review and in silico analysis of reported data on STATlinked diseases, we analysed the communication pathways and interactome of the seven STATs in major cancer categories and proposed rational targeting approaches for therapeutic intervention to disrupt critical pathways and addictions to hyperactive JAK/STAT in neoplastic states. Although all STATs follow a similar molecular activation pathway, STAT1, STAT2, STAT4 and STAT6 exert specific biological profiles associated with a more restricted pattern of activation by cytokines. STAT3 and STAT5A as well as STAT5B have pleiotropic roles in the body and can act as critical oncogenes that promote many processes involved in cancer development. STAT1, STAT3 and STAT5 also possess tumour suppressive action in certain mutational and cancer type context. Here, we demonstrated member-specific STAT activity in major cancer types. Through systems biology approaches, we found surprising roles for EGFR family members, sex steroid hormone receptor ESR1 interplay with oncogenic STAT function and proposed new drug targeting approaches of oncogenic STAT pathway addiction.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

JAK‐STAT core cancer pathway: An integrative cancer interactome analysis

Erdogan

Radu

Orlova

et al. 2022

J Cellular Molecular Medi

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“…Interestingly, transcriptome analysis revealed upregulation of Stat1 mRNA levels in OP9 and increased expression of Stat3 and Stat5 in NIH/3T3 cells. Active STAT3 and STAT5 signaling are known to increase proliferation in different cellular contexts [68][69][70][71], while STAT1 mainly acts as an antiproliferative factor [72][73][74]. Induction of proliferation in response to huOSM was also demonstrated to be related to STAT3 activation [47], whereas growth-inhibitory effects of huOSM have been found to be mediated by JAK3 and STAT1 activation [41].…”

Section: Discussionmentioning

confidence: 98%

Murine Oncostatin M Has Opposing Effects on the Proliferation of OP9 Bone Marrow Stromal Cells and NIH/3T3 Fibroblasts Signaling through the OSMR

Jakob

Müller

Rassner

et al. 2021

IJMS

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The IL-6 family cytokine Oncostatin M (OSM) is involved in cell development, growth, hematopoiesis, inflammation, and cancer. Intriguingly, OSM has proliferative and antiproliferative effects depending on the target cell. The molecular mechanisms underlying these opposing effects are not fully understood. Previously, we found OSM upregulation in different myeloproliferative syndromes. However, OSM receptor (OSMR) expression was detected on stromal cells but not the malignant cells themselves. In the present study, we, therefore, investigated the effect of murine OSM (mOSM) on proliferation in stromal and fibroblast cell lines. We found that mOSM impairs the proliferation of bone marrow (BM) stromal cells, whereas fibroblasts responded to mOSM with increased proliferation. When we set out to reveal the mechanisms underlying these opposing effects, we detected increased expression of the OSM receptors OSMR and LIFR in stromal cells. Interestingly, Osmr knockdown and Lifr overexpression attenuated the OSM-mediated effect on proliferation in both cell lines indicating that mOSM affected the proliferation signaling mainly through the OSMR. Furthermore, mOSM induced activation of the JAK-STAT, PI3K-AKT, and MAPK-ERK pathways in OP9 and NIH/3T3 cells with differences in total protein levels between the two cell lines. Our findings offer new insights into the regulation of proliferation by mOSM.

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“…Existing evidence suggests that JAK-STAT signaling members may ultimately serve as diagnostic markers stratifying patients that may benefit from more targeted therapeutic approaches that modulate downstream targets, rather than upstream JAK-STAT pathway regulators [ 42 ]. Targeting oncogenic transcription factors of the STAT family has been suggested as powerful approach potentially modulating gene regulatory processes including chromatin remodeling [ 43 ]. In contrast to other tumor entities, PD-L1 blockage did not significantly prolong HCC patient survival, suggesting that PD-L1/PD-1 axis blockade alone may not be sufficient to initiate adequate levels of anticancer immunity in HCC [ 44 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

STAT1 and STAT3 Exhibit a Crosstalk and Are Associated with Increased Inflammation in Hepatocellular Carcinoma

Ploeger

Schreck

Huth

et al. 2022

Cancers

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Liver cancers, which are mostly hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are very aggressive tumors with poor prognosis. Therapeutic options with curative intent are largely limited to surgery and available systemic therapies show limited benefit. Signal transducer and activator of transcription 1 (STAT1) and 3 (STAT3) are key transcription factors activated by pro-inflammatory cytokines such as interferon-γ (IFN-γ) and interleukin-6 (IL-6). In this study, we combined in vitro cell culture experiments and immunohistochemical analyses of human HCC (N = 124) and CCA (N = 138) specimens. We observed that in the absence of STAT3, IL-6 induced the activation of STAT1 and its target genes suggesting that IL-6 derived from the tumor microenvironment may activate both STAT1 and STAT3 target genes in HCC tumor cells. In addition, STAT1 and STAT3 were highly activated in a subset of HCC, which exhibited a high degree of infiltrating CD8- and FOXP3-positive immune cells and PD-L1 expression. Our results demonstrate that STAT1 and STAT3 are expressed and activated in HCC and tumor infiltrating immune cells. In addition, HCC cases with high STAT1 and STAT3 expression also exhibited a high degree of immune cell infiltration, suggesting increased immunological tolerance.

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Targeting STAT3 and STAT5 in Cancer

Abstract: Insights into the mutational landscape of the human cancer genome coding regions defined about 140 distinct cancer driver genes in 2013, which approximately doubled to 300 in 2018 following advances in systems cancer biology studies [...]

Cited by 8 publications

References 56 publications

JAK‐STAT core cancer pathway: An integrative cancer interactome analysis

JAK‐STAT core cancer pathway: An integrative cancer interactome analysis

Murine Oncostatin M Has Opposing Effects on the Proliferation of OP9 Bone Marrow Stromal Cells and NIH/3T3 Fibroblasts Signaling through the OSMR

STAT1 and STAT3 Exhibit a Crosstalk and Are Associated with Increased Inflammation in Hepatocellular Carcinoma

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