LINC00665 interacts with BACH1 to activate Wnt1 and mediates the M2 polarization of tumor-associated macrophages in GC.

Gastric cancer (GC) remains one of the prevalent causes of cancer-related deaths globally. Long non-coding RNAs (lncRNAs) have been associated with different cancers. The polarization of macrophages towards the M2 (alternatively activated) phenotype promotes immunologic tolerance and can induce gastric tumorigenesis. Thus far, lncRNAs have been shown to modulate the differentiation of immune cells. Here, we investigated the biological effects of LINC00665 on the progression of GC and explored the mechanisms underlying its ability to mediate the polarization of macrophages towards the M2 phenotype. We report that the levels of LINC00665 were increased in GC tissues. Furthermore, this increase in LINC00665 expression could be associated with decreased overall survival (OS), progression-free survival (PFS), and post-progression survival (PPS). Using cell-based macrophage polarization models, we demonstrated that LINC00665 upregulation in GC cells facilitated the polarization of macrophages towards the M2 but not M1 (classically activated) phenotype. Furthermore, the loss of LINC00665 prevented the M2 polarization of macrophages. Mechanically, we identified that Wnt1 was the downstream target of LINC00665. Additionally, LINC00665 could directly interact with the transcription factor BTB domain and CNC homology 1 (BACH1). The interaction between LINC00665 and BACH1 resulted in the activation and binding of BACH1 to the Wnt1 promoters. Furthermore, BACH1 silencing could inhibit GC progression, which highlighted a crucial role for BACH1 in LINC00665-mediated Wnt1 activation. In addition, genetic Wnt1 overexpression effectively abolished the repression of Wnt signaling after BACH1 depletion and mediated GC development by supporting M2 macrophage polarization. In conclusion, we report that LINC00665 modulates M2 macrophage polarization and suggest that it may facilitate macrophage-dependent GC progression.

miR­19a promotes vascular smooth muscle cell proliferation, migration and invasion through regulation of Ras homolog family member B.

Diabetic patients with high glucose exhibit vascular smooth muscle cell (VSMC) alteration. Thrombotic disease is related to erosion of an unstable plaque, the instability of which leads to ruptures, for example, a thin fibrous cap derived from VSMCs. VSMC proliferation, migration and invasion are related to thrombotic diseases, including atherosclerosis. MicroRNA­19a (miR­19a) has been reported to have pleiotropic functions in cancer cell survival, apoptosis and migration. The present study aimed to investigate the effect of miR­19a on VSMC proliferation, migration and invasion, and its mechanism. Cell Counting Kit­8 and a propidium iodide kit were used to determine the proliferation and cycle of VSMCs. A cell migration assay was performed by scratching and Matrigel was used in a cell invasion assay. miR­19a binding to Ras homolog family member B (RHOB), and their protein and mRNA expressions were determined by performing a dual luciferase assay, western blotting and reverse transcription­quantitative PCR, respectively. It was demonstrated that miR­19a promoted the proliferation, migration and invasion of VSMCs, promoted the expressions of dual specificity phosphatase Cdc25A (CDC25A), cyclinD1, matrix metalloproteinase (MMP)­2, MMP­9, α­smooth muscle actin (α­SMA) and smooth muscle 22α (SM22α), and inhibited suppressor of cytokine signaling 3 and RHOB expressions in VSMCs, while miR­19a had no effect on the expression of T­cell intracellular antigen­1. The miR­19a site bound to the RHOB gene position and inhibited RHOB to promote VSMC proliferation, invasion and migration, and increased MMP­2, MMP­9, α­SMA and SM22α expressions. The present study suggested that miR­19a could promote VSMC proliferation, migration and invasion via the cyclinD1/CDC25A and MMP/α­SMA/SM22α signaling pathways. Moreover, miR­19a promoted proliferation, migration and invasion via the MMP/α­SMA/SM22α signaling pathway by inhibiting RHOB, suggesting that miR­19a is a possible regulatory factor of RHOB.