The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway was discovered more than a quarter-century ago. As a fulcrum of many vital cellular processes, the JAK/STAT pathway constitutes a rapid membrane-to-nucleus signaling module and induces the expression of various critical mediators of cancer and inflammation. Growing evidence suggests that dysregulation of the JAK/STAT pathway is associated with various cancers and autoimmune diseases. In this review, we discuss the current knowledge about the composition, activation, and regulation of the JAK/STAT pathway. Moreover, we highlight the role of the JAK/STAT pathway and its inhibitors in various diseases.

The JAK/STAT signaling pathway: from bench to clinic.

Non-enzymatic chitinase-3 like-protein-1 (CHI3L1) belongs to glycoside hydrolase family 18. It binds to chitin, heparin, and hyaluronic acid, and is regulated by extracellular matrix changes, cytokines, growth factors, drugs, and stress. CHI3L1 is synthesized and secreted by a multitude of cells including macrophages, neutrophils, synoviocytes, chondrocytes, fibroblast-like cells, smooth muscle cells, and tumor cells. It plays a major role in tissue injury, inflammation, tissue repair, and remodeling responses. CHI3L1 has been strongly associated with diseases including asthma, arthritis, sepsis, diabetes, liver fibrosis, and coronary artery disease. Moreover, following its initial identification in the culture supernatant of the MG63 osteosarcoma cell line, CHI3L1 has been shown to be overexpressed in a wealth of both human cancers and animal tumor models. To date, interleukin-13 receptor subunit alpha-2, transmembrane protein 219, galectin-3, chemo-attractant receptor-homologous 2, and CD44 have been identified as CHI3L1 receptors. CHI3L1 signaling plays a critical role in cancer cell growth, proliferation, invasion, metastasis, angiogenesis, activation of tumor-associated macrophages, and Th2 polarization of CD4+ T cells. Interestingly, CHI3L1-based targeted therapy has been increasingly applied to the treatment of tumors including glioma and colon cancer as well as rheumatoid arthritis. This review summarizes the potential roles and mechanisms of CHI3L1 in oncogenesis and disease pathogenesis, then posits investigational strategies for targeted therapies.

/pdf/chitinase-3-like-protein-1-function-and-its-role-in-diseases-247obcg7cp.pdf

Chitinase-3 like-protein-1 function and its role in diseases.

The conversion of cells with an epithelial phenotype into cells with a mesenchymal phenotype, referred to as epithelial-mesenchymal transition, is a critical process for embryonic development that also occurs in adult life, particularly during tumour progression. Tumour cells undergoing epithelial-mesenchymal transition acquire the capacity to disarm the body's antitumour defences, resist apoptosis and anticancer drugs, disseminate throughout the organism, and act as a reservoir that replenishes and expands the tumour cell population. Epithelial-mesenchymal transition is therefore becoming a target of prime interest for anticancer therapy. Here, we discuss the screening and classification of compounds that affect epithelial-mesenchymal transition, highlight some compounds of particular interest, and address issues related to their clinical application.

Epithelial–mesenchymal transition: a new target in anticancer drug discovery

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates various biological processes, including proliferation, metastasis, angiogenesis, immune response, and chemoresistance. In normal cells, STAT3 is tightly regulated to maintain a transiently active state, while persistent STAT3 activation occurs frequently in cancers, associating with a poor prognosis and tumor progression. Targeting the STAT3 protein is a potentially promising therapeutic strategy for tumors. Although none of the STAT3 inhibitors has been marketed yet, a few of them have succeeded in entering clinical trials. This Review aims to systematically summarize the progress of the last 5 years in the discovery of directive STAT3 small-molecule inhibitors and degraders, focusing primarily on their structural features, design strategies, and bioactivities. We hope this Review will shed light on future drug design and inhibitor optimization to accelerate the discovery process of STAT3 inhibitors or degraders.

Recent Update on Development of Small-Molecule STAT3 Inhibitors for Cancer Therapy: From Phosphorylation Inhibition to Protein Degradation.

Epithelial-to-mesenchymal transition (EMT) mechanism is responsible for metastasis of tumor cells and their spread to various organs and tissues of body, providing undesirable prognosis. In addition to migration, EMT increases stemness and mediates therapy resistance. Hence, pathways involved in EMT regulation should be highlighted. STAT3 is an oncogenic pathway that can elevate growth rate and migratory ability of cancer cells and induce drug resistance. The inhibition of STAT3 signaling impairs cancer progression and promotes chemotherapy-mediated cell death. Present review focuses on STAT3 and EMT interaction in modulating cancer migration. First of all, STAT3 is an upstream mediator of EMT and is able to induce EMT-mediated metastasis in brain tumors, thoracic cancers and gastrointestinal cancers. Therefore, STAT3 inhibition significantly suppresses cancer metastasis and improves prognosis of patients. EMT regulators such as ZEB1/2 proteins, TGF-β, Twist, Snail and Slug are affected by STAT3 signaling to stimulate cancer migration and invasion. Different molecular pathways such as miRNAs, lncRNAs and circRNAs modulate STAT3/EMT axis. Furthermore, we discuss how STAT3 and EMT interaction affects therapy response of cancer cells. Finally, we demonstrate targeting STAT3/EMT axis by anti-tumor agents and clinical application of this axis for improving patient prognosis. 

STAT3-EMT axis in tumors: modulation of cancer metastasis, stemness and therapy response.

Glioblastoma multiforme (GBM) is one of the most malignant and aggressive tumors and has a very poor prognosis, with a median survival time of less than 2 years. Once recurrence develops, there are few therapeutic approaches to control the growth of glioblastoma. In particular, temozolomide (TMZ)-resistant (TMZ-R) GBM is very difficult to treat, and a novel approach to overcome resistance is eagerly awaited. Previously, we reported a novel small molecule inhibitor of STAT3 dimerization, STX-0119, as a cancer therapeutic. In the current study, the efficacy of STX-0119 was evaluated against our established TMZ-resistant U87 cell line using quantitative PCR-based gene expression analysis, in vitro assay and animal experiments. The growth inhibitory effect of STX-0119 on U87 and TMZ-R U87 cells was moderate (IC₅₀, 34 and 45 µM, respectively). In particular, STX-0119 did not show significant inhibition of U87 tumor growth; however, it suppressed the growth of the TMZ-R U87 tumor in nude mice by more than 50%, and prolonged the median survival time compared to the control group. Quantitative PCR revealed that YKL-40, MAGEC1, MGMT, several EMT genes, mesenchymal genes and STAT3 target genes were upregulated, but most of those genes were downregulated by STX-0119 treatment. Furthermore, the invasive activity of TMZ-R U87 cells was significantly inhibited by STX-0119. YKL-40 levels in TMZ-R U87 cells and their supernatants were significantly decreased by STX-0119 administration. These results suggest that STX-0119 is an efficient therapeutic to overcome TMZ resistance in recurrent GBM tumors, and could be the next promising compound leading to survival prolongation, and YKL-40 may be a possible surrogate marker for STAT3 targeting.

/pdf/effect-of-the-stat3-inhibitor-stx-0119-on-the-proliferation-14q5fu0zka.pdf

Effect of the STAT3 inhibitor STX-0119 on the proliferation of a temozolomide-resistant glioblastoma cell line

The frequent recurrence of glioblastoma multiforme (GBM) after standard treatment with temozolomide (TMZ) is a crucial issue to be solved in the clinical field. O6‑methylguanine‑DNA methyltransferase (MGMT) is considered one of the major mechanisms involved in TMZ resistance. However, some important mechanisms for TMZ resistance other than MGMT have recently been identified. In the present study, we established a TMZ-resistant (TMZ-R) U87 glioblastoma cell line in vitro and in vivo and investigated novel targeting molecules other than MGMT in those cells. The TMZ-R U87 glioblastoma cell line was established in vitro and in vivo. TMZ-R U87 cells showed a more invasive activity and a shorter survival time in vivo. Gene expression analysis using DNA microarray and quantitative PCR (qPCR) demonstrated that YKL‑40, MAGEC1 and MGMT mRNA expression was upregulated 100-, 83- and 6-fold, respectively in the TMZ-R U87 cell line. Western blot analysis and qPCR demonstrated that STAT3 phosphorylation, STAT3 target genes and stem cell and mesenchymal marker genes were upregulated to a greater extent in the TMZ‑resistant cell line. Notably, short hairpin (sh)RNA‑based inhibition against the YKL‑40 gene resulted in moderate growth inhibition in the resistant cells in vitro and in vivo. Additionally, YKL‑40 gene inhibition exhibited significant suppression of the invasive activity and particularly partially restored the sensitivity to TMZ. Therefore, YKL‑40 may be a novel key molecule in addition to MGMT, that is responsible for TMZ resistance in glioblastoma cell lines and could be a new target to overcome TMZ resistance in recurrent glioblastomas in the future.

/pdf/ykl-40-downregulation-is-a-key-factor-to-overcome-2zal5vbsdo.pdf

YKL-40 downregulation is a key factor to overcome temozolomide resistance in a glioblastoma cell line.

Local recurrence is a major clinical issue following surgical resection in head and neck cancer, and the dissemination and lymph node metastasis of minimal residual disease is relatively difficult to treat due to the lack of suitable therapeutic approaches. In the present study, we developed and evaluated a novel immunotherapy using a skin flap transfer treated with sensitized dendritic cells (DC), termed the “immuno-flap,” in a rat tumor model. After the local round area of skin was resected, SCC-158 cells (a rat head and neck cancer cell line) were inoculated into the muscle surface; lastly, the groin skin flap injected with mature DC was overlaid. Two weeks after the second DC injection, systemic immunological reactions and tumor size were measured. The DC-treated group showed a significant reduction in tumor size compared with the control. Although the induction of CTL activity in spleen cells was marginal, Th1 cytokines such as interleukin-2 and interferon-γ were elevated in the DC-treated group. These results suggest that a novel immunotherapy based on the immuno-flap method has the potential for clinical application to prevent the local recurrence of head and neck cancer patients.

Immunologically augmented skin flap as a novel dendritic cell vaccine against head and neck cancer in a rat model

Background: Signal transducer and activator of transcription (STAT)3 is involved in a metabolic shift in cancer cells, the Warburg effect through its pro-oncogenic activity. To develop efficient STAT3 inhibitors against cancer cells, novel proteomic and metabolic target molecules need to be explored using multi-omics approaches in the context of STAT3 gene inhibition-mediated tumor growth suppression. Materials and Methods: We found that short hairpin (sh)RNA-mediated STAT3 inhibition suppressed tumor growth in a highly STAT3-activated lymphoma cell line, SCC-3 cells, and we investigated the effect of STAT3 inhibition on metabolic switching using 2-dimensional differential gel electrophoresis and capillary electrophoresis- time of flight-mass spectrometry. Results: We identified latexin as a proteomic marker candidate and metabolic enzymes including fructose-bisphosphate aldolase A (ALDOA) as a metabolic marker candidate for STAT3- targeting therapy using STAT3-specific shRNA gene transduction. In particular, latexin expression was up- regulated in four STAT3-activated cancer cell lines including SCC-3 transduced with STAT3-specific shRNA. The up- regulation of latexin was identified in SCC-3 tumors transplanted to nude mice after treatment with STAT3 inhibitor. Conclusion: Our results suggest that STAT3 inactivation reverses the glycolytic shift by down-regulating key enzymes and that it induces up-regulation of latexin as a tumor-suppressor molecule, which partially results in cancer cell apoptosis and tumor growth suppression.

Effect of STAT3 Inhibition on the Metabolic Switch in a Highly STAT3-activated Lymphoma Cell Line

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Effect of the STAT3 inhibitor STX-0119 on the proliferation of a temozolomide-resistant glioblastoma cell line

YKL-40 downregulation is a key factor to overcome temozolomide resistance in a glioblastoma cell line.

Immunologically augmented skin flap as a novel dendritic cell vaccine against head and neck cancer in a rat model

Effect of STAT3 Inhibition on the Metabolic Switch in a Highly STAT3-activated Lymphoma Cell Line