BAF53A, an important subunit of the SWI/SNF epigenetic chromatin regulatory complex, has been implicated as the driver of diverse cancers. However, the role of BAF53A in colorectal cancer (CRC) remains poorly understood. Here, we examined the expression of BAF53A in CRC samples and observed that BAF53A was significantly upregulated in CRC tissues compared with paired adjacent normal tissues. In vitro and in vivo studies suggested that ectopic expression of BAF53A promoted colorectal cancer cell proliferation, colony formation, and tumorigenesis, whereas knockdown of BAF53A hindered these cellular functions. DUSP5 (dual-specificity phosphatase 5), an ERK1/2-specific endogenous phosphatase, was expressed at low levels in CRC. We found a negative correlation between BAF53A and DUSP5 expression in a set of CRC samples. Mechanistic studies revealed that P63 was a potential transcription repressor of DUSP5. BAF53A could interact with P63, decreasing the DUSP5 expression level and subsequently promoting ERK1/2 phosphorylation. Thus, our study provides insights into the applicability of the BAF53A-DUSP5-ERK1/2 axis as a potential therapeutic target in CRC.

Recent studies have indicated that endothelial Nod‐like receptor pyrin domain 3 (NLRP3) inflammasome activation during hypercholesterolemia (HC) triggers inflammatory inflammation and consequent atherosclerosis. However, the cell‐cell communication mechanisms between endothelium and smooth muscle cells (SMCs) during inflammation remain poorly understood. The present study hypothesized that activation of coronary endothelial NLRP3 inflammasomes during HC enhances the phenotypic transition of SMCs via exosomes to accelerate atherogenesis. In the primary cultures of carotid endothelial cells (CECs), we found that 7‐ketocholesterol (7‐Ket) treatment activated NLRP3 inflammasome as we showed previously and at the same time it led to a dose‐dependent increase in exosome release as measured by Nanoparticle Tracking Analysis (NTA). The increased exosomes from CECs were found to contain inflammasome products such as IL‐1β, which was associated with the decreased interaction of lysosome with multivesicular bodies (MVBs), as shown by the colocalization of MVB markers VPS16 with IL‐1β or Lamp‐1 under the confocal microscope. Mechanistically, we demonstrated that 7‐keto‐induced exosome secretion with IL‐1β and reduced interaction of lysosomes with MVBs could be enhanced by acid ceramidase (AC) inhibitor‐carmofur, lysosome inhibitor‐bafilomycin A1, or AC gene deletion. When arterial SMCs were incubated with the exosomes collected from CECs with inflammasome activation by 7‐Ket, their phenotypic transition to more synthetic was observed, as shown by increased vimentin or vimentin/SM22 ratio in the Western blot analysis and by enhanced cell migration as measured using wound healing assay method. These effects of purified exosomes from CECs upon NLRP3 inflammasome activation by 7‐Ket were opposite to that induced by exosomes from vehicle‐treated CECs, where decreased vimentin level and cell migration occurred. These results suggest that activation of the NLRP3 inflammasome in CECs by 7‐Ket releases its products via exosome secretion. These exosomes act on SMCs to promote their phenotypic transition to synthetic and also to enhance SMC migration. However, exosomes from CECs without treatment of 7‐Ket control SMC differentiation and reduce their migration, which may maintain normal SMC phenotype and function. Support or Funding Information Supported by HL057244, HL075316, and DK120491 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Hyperhomocysteinemia (hHcy) has been demonstrated to induce NLRP3 inflammasome activation and inflammatory exosome release in podocytes of mice, which can be enhanced by podocyte‐specific Smpd1 gene overexpression or blocked by global Smpd1 gene deletion. However, it remains unknown whether hHcy‐induced podocyte injury and glomerular inflammation are attributed to these exosomes secreted from podocytes during hHcy. In the present study, we found that exosomes extracted from urine of mice with hHcy induced by folate free (FF) diet induced podocyte injury when they were infused into the renal cortical interstitial space in both WT/WT and Smpd1‐/‐ mice, as shown by reduction of podocin and elevation of desmin in glomeruli. These exosomes from mice with hHcy also increased T‐cells in glomeruli, which was not blocked by global Smpd1 gene deletion. Functionally, proteinuria was detected in both WT/WT and Smpd1‐/‐ mice receiving these exosomes from mice with hHcy. However, infusion of urinary exosomes from mice on the normal diet (ND) had no effects on these podocyte injury and glomerular inflammatory changes. We also performed in vitro experiments with cultured podocytes. We treated murine podocytes with urinary exosomes from mice on the ND and FF diet. It was found that exosomes from mice on the FF diet produced no significant effects on podocytes compared with control exosomes if they were cultured without immune cells. If murine podocytes were co‐cultured with T‐cells, macrophages, or both, the exosomes from mice with hHcy caused significant podocyte damage as shown by reduction of podocin and elevation of desmin, but exosomes from mice on the ND failed to influence podocytes even in the presence of immune cells. These results suggest that hHcy increases urinary exosomes and these exosomes importantly contribute to podocyte injury and glomerular inflammation during hHcy.