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Esophageal squamous cell carcinoma (ESCC), one of the most common malignant tumors, is now afflicting approximately 80% of patients diagnosed with esophageal cancers. The therapeutic effect and prognosis of ESCC remain inadequate due to the unusual early symptoms and rapid malignant progression. SH2 Domain containing 4 A (SH2D4A) is downregulated in malignancies and is closely associated with tumor progression. However, neither the biological functions nor the fundamental mechanisms of SH2D4A on ESCC are known. In this study, it was found that SH2D4A is downregulated in ESCC tissues and cell lines. Incorporating immunohistochemistry and clinicopathological findings, we determined that decreased SH2D4A expression was substantially associated with adverse clinical outcomes. Overexpression of SH2D4A inhibited cell proliferation and migration, whereas suppressing SH2D4A has the opposite effect. SH2D4A mechanistically inhibited cells from proliferating and migrating through the FAK/PI3K/AKT signaling pathway. Furthermore, the results of xenograft tumor growth confirmed the preceding findings. In conclusion, our findings reveal that SH2D4A is a gene which can serve as a cancer suppressor in ESCC and may inhibits the ESCC progression by interfering with the FAK/PI3K/AKT signaling pathway. SH2D4A could act as a target for diagnostic or therapeutic purpose in ESCC. • SH2D4A acted as a tumor suppressor in ESCC. • SH2D4A was downregulated in ESCC and decreased SH2D4A expression predicted an adverse clinical outcome. • SH2D4A overexpression inhibited proliferation and migration in ESCC. • SH2D4A inhibited ESCC from proliferating and migrating through the FAK/PI3K/AKT signaling pathway. [ABSTRACT FROM AUTHOR]

Accumulating evidences indicate that circular RNAs (circRNAs) play a vital role in modulating gene expression. However, the mechanisms underlying circRNAs remain largely elusive. Here, we screened circRNA and mRNA expression profiles of bladder carcinoma (BC) using microarray analysis. We found that circRNA-MYLK and VEGFA were significantly up-regulated and co-expressed in BC. Importantly, circRNA-MYLK levels were related to the progression of stage and grade of BC. Mechanistically, we demonstrated that circRNA-MYLK could directly bind to miR-29a and relieve suppression for target VEGFA, which activated VEGFA/VEGFR2 signaling pathway. Functionally, we found that ectopically expressing circRNA-MYLK accelerated cell proliferation, migration, tube formation of HUVEC and rearranged cytoskeleton. Moreover, up-regulating circRNA-MYLK promoted epithelial-mesenchymal transition (EMT). Whereas circRNA-MYLK knockdown decreased cell proliferation, motility, and induced apoptosis. Finally, up-regulating circRNA-MYLK promoted the growth, angiogenesis and metastasis of BC xenografts. Taken together, this study demonstrated for the first time that circRNA-MYLK might function as competing endogenous RNA (ceRNA) for miR-29a, which could contribute to EMT and the development of BC through activating VEGFA/VEGFR2 and downstream Ras/ERK signaling pathway. Our data suggest that circRNA-MYLK would be a promising target for BC diagnosis and therapy. [ABSTRACT FROM AUTHOR]

Angiogenin (ANG), a member of RNase A superfamily, is the only angiogenic factor that possesses ribonucleolytic activity. Recent studies showed that the expression of ANG was elevated in various types of cancers. Accumulating evidence indicates that ANG plays an essential role in cancer progression by stimulating both cancer cell proliferation and tumor angiogenesis. Human ribonuclease inhibitor (RI), a cytoplasmic protein, is constructed almost entirely of leucine rich repeats (LRRs), which are present in a large family of proteins that are distinguished by their display of vast surface areas to foster protein–protein interactions. RI might be involved in unknown biological effects except inhibiting RNase A activity. The experiment demonstrated that RI also could suppress activity of angiogenin (ANG) through closely combining with it in vitro. PI3K/AKT/mTOR signaling pathway exerts a key role in cell growth, survival, proliferation, apoptosis and angiogenesis. We recently reported that up-regulating RI inhibited the growth and induced apoptosis of murine melanoma cells through repression of angiogenin and PI3K/AKT signaling pathway. However, ANG receptors have not yet been identified to date, its related signal transduction pathways are not fully clear and underlying interacting mechanisms between RI and ANG remain largely unknown. Therefore, we hypothesize that RI might combine with intracellular ANG to block its nuclear translocation and regulate PI3K/AKT/mTOR signaling pathway to inhibit biological functions of ANG. Here, we reported for the first time that ANG could interact with RI endogenously and exogenously by using co-immunoprecipitation (Co-IP) and GST pull-down. Furthermore, we observed the colocalization of ANG and RI in cells with immunofluorescence staining under laser confocal microscope. Moreover, through fluorescence resonance energy transfer (FRET) assay, we further confirmed that these two proteins have a physical interaction in living cells. Subsequently, we demonstrated that up-regulating ANG including ANG His37Ala mutant obviously decreased RI expression and activated phosphorylation of key downstream target molecules of PI3K/AKT/mTOR signaling pathway. Finally, up-regulating ANG led to the promotion of tumor angiogenesis, tumorigenesis and metastasis in vivo. Taken together, our data provided a novel mechanism of ANG in regulating PI3K/AKT/mTOR signaling pathway via RI, which suggested a new therapeutic target for cancer therapy. [ABSTRACT FROM AUTHOR]