STAT3 expression is associated with poor survival in non-elderly adult patients with newly diagnosed multiple myeloma

Jung, Sung-Hoon; Ahn, Seo-Yeon; Choi, Hyun-Woo; Shin, Myung‐Geun; Lee, Seung-Shin; Yang, Deok‐Hwan; Ahn, Jae‐Sook; Kim, Yeo-Kyeoung; Kim, Hyeoung-Joon; Lee, Je‐Jung

doi:10.5045/br.2017.52.4.293

Cited by 22 publications

(20 citation statements)

References 30 publications

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“…STAT3 activity promotes expansion and activation of myeloid-derived suppressor cells (MDSCs), which mediate immunosuppression and facilitate tumor progression in the MM bone marrow microenvironment [112][113][114]. Expression of phosphorylated STAT3 is associated with poor prognosis and survival in MM patients [115]. Several preclinical studies have demonstrated that inhibition of JAK/STAT3 signaling alone or in combination with other antitumor reagents inhibits MM cell growth both in vitro and in vivo [116][117][118][119].…”

Section: Multiple Myelomamentioning

confidence: 99%

STAT3 Activation and Oncogenesis in Lymphoma

Zhu

Wang²,

2019

Cancers

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Signal transducer and activator of transcription 3 (STAT3) is an important and the most studied transcription factor in the Janus kinase (JAK)/STAT signaling pathway. STAT3 mediates the expression of various genes that play a critical role in many cellular and biological processes, such as cell proliferation, survival, differentiation, migration, angiogenesis, and inflammation. STAT3 and associated JAKs are activated and tightly regulated by a variety of cytokines and growth factors and their receptors in normal immune responses. However, abnormal expression of STAT3 leads to its constitutive activation, which promotes malignant transformation and tumor progression through oncogenic gene expression in numerous human cancers. Human lymphoma is a heterogeneous malignancy of T and B lymphocytes. Constitutive signaling by STAT3 is an oncogenic driver in several types of B-cell lymphoma and most of T-cell lymphomas. Aberrant STAT3 activation can also induce inappropriate expression of genes involved in tumor immune evasion such as PD-L1. In this review, we focus on the oncogenic role of STAT3 in human lymphoma and highlight potential therapeutic intervention by targeting JAK/STAT3 signaling.

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Section: Multiple Myelomamentioning

confidence: 99%

STAT3 Activation and Oncogenesis in Lymphoma

Zhu

Wang²,

2019

Cancers

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“…STAT3 is closely associated with inflammation, tumorigenesis and MM cell survival 34 and it is induced by IL6 35 which, as we found herein, is over-secreted following non-lethal proteasome inhibition in MM cells. STAT3 has been associated with poor survival of MM patients 36 and resistance to lenalidomide, 37 while its inhibition suppressed MM cell growth 38 suggesting that it represents a promising therapeutic target in MM. 39 Consistently, it was found that MM exosomes establish a favourable bone marrow microenvironment which enhanced angiogenesis and immunosuppression through activation of the STAT3 pathway, 40 as well as that STAT3 establishes an immunosuppressive microenvironment during the early stages of breast carcinogenesis to promote tumour growth and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Non‐lethal proteasome inhibition activates pro‐tumorigenic pathways in multiple myeloma cells

Skorda

Sklirou

Sakellaropoulos

et al. 2019

J Cellular Molecular Medi

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Multiple myeloma (MM) is a haematological malignancy being characterized by clonal plasma cell proliferation in the bone marrow. Targeting the proteasome with specific inhibitors (PIs) has been proven a promising therapeutic strategy and PIs have been approved for the treatment of MM and mantle‐cell lymphoma; yet, while outcome has improved, most patients inevitably relapse. As relapse refers to MM cells that survive therapy, we sought to identify the molecular responses induced in MM cells after non‐lethal proteasome inhibition. By using bortezomib (BTZ), epoxomicin (EPOX; a carfilzomib‐like PI) and three PIs, namely Rub999, PR671A and Rub1024 that target each of the three proteasome peptidases, we found that only BTZ and EPOX are toxic in MM cells at low concentrations. Phosphoproteomic profiling after treatment of MM cells with non‐lethal (IC10) doses of the PIs revealed inhibitor‐ and cell type‐specific readouts, being marked by the activation of tumorigenic STAT3 and STAT6. Consistently, cytokine/chemokine profiling revealed the increased secretion of immunosuppressive pro‐tumorigenic cytokines (IL6 and IL8), along with the inhibition of potent T cell chemoattractant chemokines (CXCL10). These findings indicate that MM cells that survive treatment with therapeutic PIs shape a pro‐tumorigenic immunosuppressive cellular and secretory bone marrow microenvironment that enables malignancy to relapse.

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“…Pharmacological agents such as curcumin, piperlongumine, icaritin and LLL12 which blocked STAT3 phosphorylation were reported to suppress primary MM cell viability and/or MM tumor growth in animal models [ 22 , 56 , 57 , 58 ]. Clinically, a high pSTAT3 level has been reported to correlate with poorer progress-free survival and overall survival in newly diagnosed MM patients [ 59 ]. While constitutively high STAT3 activity was observed in >50% of primary MM samples, MM cell lines typically showed no evidence or a low level of STAT3 activity [ 22 , 60 ].…”

Section: Discussionmentioning

confidence: 99%

Constitutive Activation of STAT3 in Myeloma Cells Cultured in a Three-Dimensional, Reconstructed Bone Marrow Model

Huang

Molavi

Alshareef

et al. 2018

Cancers

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Malignant cells cultured in three-dimensional (3D) models have been found to be phenotypically and biochemically different from their counterparts cultured conventionally. Since most of these studies employed solid tumor types, how 3D culture affects multiple myeloma (MM) cells is not well understood. Here, we compared MM cells (U266 and RPMI8226) in a 3D culture model with those in conventional culture. While the conventionally cultured cells were present in single cells or small clusters, MM-3D cells grew in large spheroids. We discovered that STAT3 was the pathway that was more activated in 3D in both cell lines. The active form of STAT3 (phospho-STAT3 or pSTAT3), which was absent in MM cells cultured conventionally, became detectable after 1–2 days in 3D culture. This elevated pSTAT3 level was dependent on the 3D environment, since it disappeared after transferring to conventional culture. STAT3 inhibition using a pharmacological agent, Stattic, significantly decreased the cell viability of MM cells and sensitized them to bortezomib in 3D culture. Using an oligonucleotide array, we found that 3D culture significantly increased the expression of several known STAT3 downstream genes implicated in oncogenesis. Since most primary MM tumors are naturally STAT3-active, studies of MM in 3D culture can generate results that are more representative of the disease.

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STAT3 expression is associated with poor survival in non-elderly adult patients with newly diagnosed multiple myeloma

Cited by 22 publications

References 30 publications

STAT3 Activation and Oncogenesis in Lymphoma

STAT3 Activation and Oncogenesis in Lymphoma

Non‐lethal proteasome inhibition activates pro‐tumorigenic pathways in multiple myeloma cells

Constitutive Activation of STAT3 in Myeloma Cells Cultured in a Three-Dimensional, Reconstructed Bone Marrow Model

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