miR-204 inhibits angiogenesis and promotes sensitivity to cetuximab in head and neck squamous cell carcinoma cells by blocking JAK2-STAT3 signaling.

This study aims to investigate the roles of miR-204 in tumor angiogenesis of head and neck squamous cell carcinoma (HNSCC). Here, we found that miR-204 level was reduced in HNSCC tissues relative to that in normal adjacent tissues. Overexpression of miR-204 promoted tumor angiogenesis in HNSCC cells. Mechanistically, JAK2 was identified as a direct target of miR-204, and miR-204 overexpression blocked JAK2/STAT3 pathway. Moreover, overexpression of JAK2 attenuated the inhibition of miR-204 on tumor angiogenesis of HNSCC. Furthermore, overexpression of miR-204 enhanced sensitivity of cetuximab in HNSCC cells, this effect was attenuated by JAK2 overexpression too. Importantly, JAK2 expression was negatively correlated with miR-204 level in HNSCC tissues. Therefore, miR-204 acts as a tumor suppressor by blocking JAK2/STAT3 pathway in HNSCC cells.

Wu Q ，Zhao Y ，Wang P 《-》

Inhibition of JAK2/STAT3 reduces tumor-induced angiogenesis and myeloid-derived suppressor cells in head and neck cancer.

Angiogenesis is an essential event in tumor growth and metastasis, and immune system also contributes to the tumor evasion. Emerging evidences have suggested the bidirectional link between angiogenesis and immunosuppression. Myeloid-derived suppressor cell (MDSC) is a kind of immunosuppressive cells and plays an important role in this process. However, the actual regulatory mechanisms of angiogenesis and MDSCs in head and neck squamous cell carcinoma (HNSCC) were unclear. In this study, through analyzing the immunohistochemistry staining of human HNSCC tissue microarray, we found that the microvascular density (MVD) was significantly increased in HNSCC patients. We also characterized angiogenic factors p-STAT3, VEGFA, CK2, and MDSCs marker CD11b in HNSCC tissue array, and found the close expression correlation among these markers. To determine the role of JAK2/STAT3 pathway in tumor microenvironment of HNSCC, we utilized AG490 (an inhibitor of JAK2/STAT3) for further research. Results showed that inhibition of JAK2/STAT3 suppressed angiogenesis by decreasing VEGFA and HIF1-α both in vitro and vivo. Moreover, in HNSCC transgenic mouse model, inhibiting JAK2/STAT3 not only suppressed angiogenesis but also reduced MDSCs in the tumor microenvironment through suppressing VEGFA and CK2. Our findings demonstrated the close relationship between angiogenesis and MDSCs in HNSCC, and inhibition of JAK2/STAT3 could reduce tumor-induced angiogenesis and decrease MDSCs.

Liu JF ，Deng WW ，Chen L ，Li YC ，Wu L ，Ma SR ，Zhang WF ，Bu LL ，Sun ZJ ... -  《-》

p53-targeted lincRNA-p21 acts as a tumor suppressor by inhibiting JAK2/STAT3 signaling pathways in head and neck squamous cell carcinoma.

Jin S ，Yang X ，Li J ，Yang W ，Ma H ，Zhang Z ... -  《Molecular Cancer》

MicroRNA-204 deregulation in lung adenocarcinoma controls the biological behaviors of endothelial cells potentially by modulating Janus kinase 2-signal transducer and activator of transcription 3 pathway.

MicroRNAs (miRNAs) have been implicated in a wide range of biological processes including angiogenesis. MiR-204 was identified as a tumor suppressor in multiple cancer types, including lung adenocarcinoma. However, the function of miR-204 in lung tumor angiogenesis remains unknown. In this study, we found that the miR-204 expression was decreased in lung adenocarcinoma based on the cancer genome atlas (TCGA) analysis and gain-of-function experiment showed that miR-204 promoted cancer cell apoptosis and suppressed cell proliferation, migration in vitro and tumor growth in vivo. Functionally, both the tube formation and migration abilities of human umbilical vein endothelial cells (HUVECs) were suppressed by conditioned media from lung cancer A549 cells with miR-204 overexpression. Meanwhile, these conditioned media inhibited proliferation and promoted apoptosis in HUVECs. The key angiogenesis inducer hypoxia inducible factor-1α (HIF1α) and the pro-angiogenic mediators vascular endothelial growth factor and platelet-derived growth factor were decreased in A549 cells transfected with miR-204 mimics. Mechanistically, miR-204 could target Janus kinase 2 (JAK2) and further impaired signal transducer and activator of transcription 3 both in vitro and in vivo. Inhibition of JAK2 or signal transducer and activator of transcription 3 (STAT3) activity with small chemical inhibitors in A549 cells impaired lung adenocarcinoma angiogenesis in vitro. Meanwhile, conditional media from interleukin 6-treated lung normal epithelial cells significantly promoted tube formation of HUVEC, which was disturbed by miR-204 overexpression. Taken together, our findings demonstrate that miR-204 attenuates angiogenesis in lung adenocarcinoma potentially via JAK2-STAT3 pathway. Clinically, the miR-204/JAK2/STAT3 signaling pathway is a putative therapeutic target in lung adenocarcinoma. © 2017 IUBMB Life, 70(1):81-91, 2018.

Liu X ，Gao X ，Zhang W ，Zhu T ，Bi W ，Zhang Y ... -  《-》

TGF-β-induced STAT3 overexpression promotes human head and neck squamous cell carcinoma invasion and metastasis through malat1/miR-30a interactions.

Aberrant signal transducer and activator of transcription 3 (STAT3) signaling is a critical factor that drives the invasion and metastasis of head and neck squamous cell carcinoma (HNSCC). However, the underlying mechanisms of STAT3 overexpression and regulation of HNSCC metastasis remain unknown. In the current study, we demonstrated that upregulated TGF-β may promote epithelial-mesenchymal transition (EMT) through STAT3 activation. In addition, we explored the contributions of STAT3 to HNSCC with a specific focus on its transcriptional regulation and its interaction with the long noncoding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (malat1). Chromatin immunoprecipitation (ChIP) and luciferase reporter assays revealed that STAT3 could bind to the malat1 promoter region and transcriptionally activate malat1 expression; then, malat1 interacted reciprocally with miR-30a, inducing EMT and accelerating HNSCC metastasis. In summary, our discoveries illuminate how aberrant STAT3 activation confers an oncogenic function in HNSCC and therefore may provide a theoretical foundation for STAT3 as a therapeutic target in HNSCC.

Wang Y ，Wu C ，Zhang C ，Li Z ，Zhu T ，Chen J ，Ren Y ，Wang X ，Zhang L ，Zhou X ... -  《-》