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.

A ubiquitously expressed cytokine, transforming growth factor-beta (TGF-β) plays a significant role in various ongoing cellular mechanisms. The gain or loss-of-function of TGF-β and its downstream mediators could lead to a plethora of diseases includes tumorigenesis. Specifically, at the early onset of malignancy TGF-β act as tumour suppressor and plays a key role in clearing malignant cells by reducing the cellular proliferation and differentiation thus triggers the process of apoptosis. Subsequently, TGF-β at an advanced stage of malignancy promotes tumorigenesis by augmenting cellular transformation, epithelial-mesenchymal-transition invasion, and metastasis. Besides playing the dual roles, depending upon the stage of malignancy, TGF-β also regulates cell fate through immune and stroma components. This oscillatory role of TGF-β to fight against cancer or act as a traitor to collaborate and crosstalk with other tumorigenic signaling pathways and its betrayal within the cell depends upon the cellular context. Therefore, the current review highlights and understands the dual role of TGF-β under different cellular conditions and its crosstalk with other signaling pathways in modulating cell fate.

Transforming Growth Factor-Beta (TGF-β) Signaling in Cancer-A Betrayal Within

Hypoxia is an important process that involved in the tumor microenvironment. In addition, hypoxic tumor cell-derived exosomes could promote tumor growth and angiogenesis. Thus, we aimed to investigate whether exosomes could regulate tumor development and progression under hypoxia in breast cancer.The level of SNHG1 in hypoxic breast cancer cells and exosomes derived from hypoxic breast cancer cells was determined by real-time qPCR assay. Bioinformatics prediction and dual-luciferase reporter assays were used to determine the interaction between SNHG1, miR-216b-5p and JAK2.We found that comparing with exosomes derived from normoxia breast cancer cells, exosomes derived from hypoxic breast cancer cells could promote the proliferation, migration and angiogenesis of human umbilical vein endothelial cells (HUVECs). In addition, SNHG1 level was significantly upregulated in exosomes derived from hypoxic breast cancer cells. Moreover, exosome-mediated delivery of SNHG1 siRNA3 markedly reversed the effects of exosome-mediated delivery of SNHG1 on HUVECs. Mechanically, SNHG1 could increase the level of JAK2 by competitively binding to miR-216b-5p. Additionally, exosome-mediated delivery of SNHG1 was found to promote breast cancer growth in vivo.Collectively, our study revealed that exosomal SNHG1 from hypoxic breast cancer cells could promote tumor angiogenesis and growth via regulating miR-216b-5p/JAK2 axis, suggesting that SNHG1 may serve as a potential therapeutic target for breast cancer. 

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Hypoxic Breast Cancer Cell-Derived Exosomal SNHG1 Promotes Breast Cancer Growth and Angiogenesis via Regulating miR-216b-5p/JAK2 Axis

Background Hypoxia is an important process that involved in the tumor microenvironment. In addition, hypoxic tumor cell-derived exosomes could promote tumor growth and angiogenesis. Thus, we aimed to investigate whether exosomes could regulate tumor development and progression under hypoxia in breast cancer. Methods The level of SNHG1 in hypoxic breast cancer cells and exosomes derived from hypoxic breast cancer cells was determined by real-time qPCR assay. Bioinformatics prediction and dual-luciferase reporter assays were used to determine the interaction between SNHG1, miR-216b-5p and JAK2. Results We found that comparing with exosomes derived from normoxia breast cancer cells, exosomes derived from hypoxic breast cancer cells could promote the proliferation, migration and angiogenesis of human umbilical vein endothelial cells (HUVECs). In addition, SNHG1 level was significantly upregulated in exosomes derived from hypoxic breast cancer cells. Moreover, exosome-mediated delivery of SNHG1 siRNA3 markedly reversed the effects of exosome-mediated delivery of SNHG1 on HUVECs. Mechanically, SNHG1 could increase the level of JAK2 by competitively binding to miR-216b-5p. Additionally, exosome-mediated delivery of SNHG1 was found to promote breast cancer growth in vivo. Conclusion Collectively, our study revealed that exosomal SNHG1 from hypoxic breast cancer cells could promote tumor angiogenesis and growth via regulating miR-216b-5p/JAK2 axis, suggesting that SNHG1 may serve as a potential therapeutic target for breast cancer.

https://www.dovepress.com/getfile.php?fileID=77429

HDAC9 (histone deacetylase 9) belongs to the class IIa family of histone deacetylases. This enzyme can shuttle freely between the nucleus and cytoplasm and promotes tissue-specific transcriptional regulation by interacting with histone and non-histone substrates. HDAC9 plays an essential role in diverse physiological processes including cardiac muscle development, bone formation, adipocyte differentiation and innate immunity. HDAC9 inhibition or activation is therefore a promising avenue for therapeutic intervention in several diseases. HDAC9 overexpression is also common in cancer cells, where HDAC9 alters the expression and activity of numerous relevant proteins involved in carcinogenesis. This review summarizes the most recent discoveries regarding HDAC9 as a crucial regulator of specific physiological systems and, more importantly, highlights the diverse spectrum of HDAC9-mediated posttranslational modifications and their contributions to cancer pathogenesis. HDAC9 is a potential novel therapeutic target, and the restoration of aberrant expression patterns observed among HDAC9 target genes and their related signaling pathways may provide opportunities to the design of novel anticancer therapeutic strategies.

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Histone deacetylase (HDAC) 9: versatile biological functions and emerging roles in human cancer

Breast cancer is the most common malignant tumor in women worldwide. Traditional ways of treatment, including radiotherapy and endocrine therapy, for breast cancer have inevitable side effects. In recent decades, targeted therapies for breast cancer have rapidly advanced and shown a promising future. The JAK/STAT signaling pathway has been shown to play important roles in tumorigenesis, maintenance and metastasis of breast cancer. Hence, many small molecule inhibitors of JAK and STAT proteins have been developed. These inhibitors exhibit potent inhibitory effects on breast cancer in both cellular and animal models, and even some of them have already been in clinical trials. This review article discussed the JAK/STAT signal transduction pathway in the pathogenesis of breast cancer, and the potential for the application of JAK/STAT inhibitors in breast cancer treatment.

Xiaonan Pang

Papers

Targeting the JAK/STAT Signaling Pathway for Breast Cancer.