Multicellular Effects of STAT3 in Non-small Cell Lung Cancer: Mechanistic Insights and Therapeutic Opportunities

Parakh, Sagun; Ernst, Matthias; Poh, Ashleigh R.

doi:10.3390/cancers13246228

Cited by 37 publications

(35 citation statements)

References 301 publications

(395 reference statements)

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“…STAT family members are both signal transducers and transcription factors [ 40 ]. Activation of STAT3 contributes to the development of many cancers [ 41 ], while the inhibition of STAT3 reportedly elicits apoptotic cell death and stimulates immune-related activities to eliminate cancer cells [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…Activation of STAT3 contributes to the development of many cancers [ 41 ], while the inhibition of STAT3 reportedly elicits apoptotic cell death and stimulates immune-related activities to eliminate cancer cells [ 41 ]. Previous research has demonstrated the importance of tumor cell-intrinsic and extrinsic STAT3 signaling, as these activities encourage angiogenesis in non-small cell lung cancer by upregulating the expression of VEGF and other growth factors [ 40 ]. In this study, our results indicated the involvement of MEK, ERK, and STAT3 phosphorylation in CCL4-mediated promotion of Angpt2 expression and angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

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The Chemokine CCL4 Stimulates Angiopoietin-2 Expression and Angiogenesis via the MEK/ERK/STAT3 Pathway in Oral Squamous Cell Carcinoma

Tsai

Yang

et al. 2022

Biomedicines

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Oral squamous cell carcinoma (OSCC) is a common malignant tumor with a poor prognosis and is a major public health burden in Taiwan. Angiogenesis, the formation of new blood vessels, promotes tumor proliferation, maintenance, and metastasis. Angiopoietin 2 (Angpt2), a mitogen with a strong angiogenic effect, is highly specific to endothelial cells and a key player in angiogenesis. The inflammatory chemokine (C-C motif) ligand 4 (CCL4) is also important in the pathogenesis and progression of cancer. In this study, an analysis of records from The Cancer Genome Atlas (TCGA) database found higher CCL4 expression in oral cancer tissue than in normal healthy tissue. CCL4 treatment of oral cancer cells upregulated Angpt2 expression and stimulated mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinase 1/2 (ERK), and signal transducer and activator of transcription 3 (STAT3) phosphorylation. Transfection of oral cancer cells with MEK, ERK, and STAT3 inhibitors and their small interfering RNAs inhibited CCL4-induced promotion of Angpt2 expression and angiogenesis. In a mouse model of OSCC, CCL4-treated cells promoted neovascularization in implanted Matrigel plugs, whereas inhibiting CCL4 expression suppressed Angpt2 expression and angiogenesis. CCL4 shows promise as a new molecular therapeutic target for inhibiting angiogenesis and metastasis in OSCC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Chemokine CCL4 Stimulates Angiopoietin-2 Expression and Angiogenesis via the MEK/ERK/STAT3 Pathway in Oral Squamous Cell Carcinoma

Tsai

Yang

et al. 2022

Biomedicines

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“…In light of the many negative effects of hyperactive STAT3 in the TME, a number of therapeutic interventions have been developed that target different stages of STAT3 signaling. Many of these drugs are already in or finishing clinical trials and have been extensively reviewed elsewhere [ 129 , 130 ]. However, we want to touch on a few of these which hold the most promise.…”

Section: Stat3 Inhibitionmentioning

confidence: 99%

“…Multiple small molecule STAT3 inhibitors have been tested in the last decade, and there are still many novel inhibitors which may one day reach clinical application [ 130 , 131 ]. One such STAT3 inhibitor, TTI-101, binds to the SH2 domain to prevent STAT3 homodimerization [ 132 ].…”

Section: Stat3 Inhibitionmentioning

confidence: 99%

Cell Type-Specific Roles of STAT3 Signaling in the Pathogenesis and Progression of K-ras Mutant Lung Adenocarcinoma

Clowers

Moghaddam

2022

Cancers

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Worldwide, lung cancer, particularly K-ras mutant lung adenocarcinoma (KM-LUAD), is the leading cause of cancer mortality because of its high incidence and low cure rate. To treat and prevent KM-LUAD, there is an urgent unmet need for alternative strategies targeting downstream effectors of K-ras and/or its cooperating pathways. Tumor-promoting inflammation, an enabling hallmark of cancer, strongly participates in the development and progression of KM-LUAD. However, our knowledge of the dynamic inflammatory mechanisms, immunomodulatory pathways, and cell-specific molecular signals mediating K-ras-induced lung tumorigenesis is substantially deficient. Nevertheless, within this signaling complexity, an inflammatory pathway is emerging as a druggable target: signal transducer and activator of transcription 3 (STAT3). Here, we review the cell type-specific functions of STAT3 in the pathogenesis and progression of KM-LUAD that could serve as a new target for personalized preventive and therapeutic intervention for this intractable form of lung cancer.

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“…As shown in Figure 6, CS3 and CS4 patients had lower IC 50 values, indicating that they may be more sensitive to these chemotherapy drugs. Previous studies have shown that inhibition of STAT3 expression may be the key to the combination of paclitaxel and cisplatin in NSCLC chemotherapy (49)(50)(51). miR-526b-3p promotes the response to cisplatin by inhibiting STAT3.…”

Section: Precision Treatment Recommendations For Luad Patientsmentioning

confidence: 99%

Multi-Omics Integrative Analysis of Lung Adenocarcinoma: An in silico Profiling for Precise Medicine

Ruan

Cheng

et al. 2022

Front. Med.

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Lung adenocarcinoma (LUAD) is one of the most common histological subtypes of lung cancer. The aim of this study was to construct consensus clusters based on multi-omics data and multiple algorithms. In order to identify specific molecular characteristics and facilitate the use of precision medicine on patients we used gene expression, DNA methylation, gene mutations, copy number variation data, and clinical data of LUAD patients for clustering. Consensus clusters were obtained using a consensus ensemble of five multi-omics integrative algorithms. Four molecular subtypes were identified. The CS1 and CS2 subtypes had better prognosis. Based on the immune and drug sensitivity predictions, we inferred that CS1 may be less responsive to immunotherapy and less sensitive to chemotherapeutic drugs. The high immune infiltration of CS2 cells may respond well to immunotherapy. Additionally, the CS2 subtype may also respond to EGFR molecular targeted therapy. The CS3 and CS4 subtypes were associated with poor prognosis. These two subtypes had more mutations, especially TP53 ones, as well as higher sensitivity to chemotherapeutics for lung cancer. However, CS3 was enriched in immune-related pathways and may respond to anti-PD1 immunotherapy. In addition, CS1 and CS4 were less sensitive to ferroptosis inhibitors. We performed a comprehensive analysis of the five types of omics data using five clustering algorithms to reveal the molecular characteristics of LUAD patients. These findings provide new insights into LUAD subtypes and potential clinical treatment strategies to guide personalized management and treatment.

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Multicellular Effects of STAT3 in Non-small Cell Lung Cancer: Mechanistic Insights and Therapeutic Opportunities

Cited by 37 publications

References 301 publications

The Chemokine CCL4 Stimulates Angiopoietin-2 Expression and Angiogenesis via the MEK/ERK/STAT3 Pathway in Oral Squamous Cell Carcinoma

The Chemokine CCL4 Stimulates Angiopoietin-2 Expression and Angiogenesis via the MEK/ERK/STAT3 Pathway in Oral Squamous Cell Carcinoma

Cell Type-Specific Roles of STAT3 Signaling in the Pathogenesis and Progression of K-ras Mutant Lung Adenocarcinoma

Multi-Omics Integrative Analysis of Lung Adenocarcinoma: An in silico Profiling for Precise Medicine

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