Exosomes are well-known key mediators of intercellular communication and contribute to various physiological and pathological processes. Their biogenesis involves four key steps, including cargo sorting, MVB formation and maturation, transport of MVBs, and MVB fusion with the plasma membrane. Each process is modulated through the competition or coordination of multiple mechanisms, whereby diverse repertoires of molecular cargos are sorted into distinct subpopulations of exosomes, resulting in the high heterogeneity of exosomes. Intriguingly, cancer cells exploit various strategies, such as aberrant gene expression, posttranslational modifications, and altered signaling pathways, to regulate the biogenesis, composition, and eventually functions of exosomes to promote cancer progression. Therefore, exosome biogenesis-targeted therapy is being actively explored. In this review, we systematically summarize recent progress in understanding the machinery of exosome biogenesis and how it is regulated in the context of cancer. In particular, we highlight pharmacological targeting of exosome biogenesis as a promising cancer therapeutic strategy.

Background: Long non-coding RNAs (lncRNAs) have been shown to play important roles in a wide range of pathophysiological processes, including cancer progression. Our previous study has shown that AFAP1-AS1 was upregulated and acted as an oncogene in hepatocellular carcinoma. However, the expression and biological functions of lncRNA AFAP1-AS1 in intrahepatic cholangiocarcinoma (CCA) remains largely unknown. Methods: The expression level of AFAP1-AS1 was measured in 56 pairs of human cholangiocarcinoma tumor tissues and corresponding adjacent normal bile duct tissues. The correlation between AFAP1-AS1 and the clinicopathological features were evaluated by chi-square test. The effects of AFAP1-AS1 on CCA cells were determined by CCK-8 assay, clone formation assay, flow cytometry and transwell assay. Finally, to determine the effect of AFAP1-AS1 on tumor growth in vivo, AFAP1-AS1 knockdowned CCLP-1 cells were subcutaneously into nude mice to evaluate tumor growth. Results: In this study, we found that lncRNA AFAP1-AS1 was increased in CCA tissues and patients with high AFAP1-AS1 expression had a shorter overall survival. SiRNA-mediated AFAP1-AS1 knockdown significantly decreased cell proliferation of the CCA cells, with downregulation of C-myc and Cycling D1 in vitro. Furthermore, AFAP1-AS1 silencing inhibited cell migration partly due to decrease the expression of MMP-2 and MMP-9. In addition, CCLP-1 cells with AFAP1-AS1 knockdown were injected into nude mice to investigate the effect of AFAP1-AS1 on the tumorigenesis in vivo. Conclusions: Taken together, our findings suggested that AFAP1-AS1 might promote the CCA progression and provided a novel potential therapeutic target for CCA.

Increasing evidence has indicated that dysregulation of long non-coding RNAs (lncRNAs) can contribute to the progression and metastasis of human cancer, including HCC. Previous studies have shown that the lncRNA AFAP1-AS1 plays a critical role in cancer. However, the roles of AFAP1-AS1 in HCC remain to be determined. In the present study, AFAP1-AS1 was found to be increased in HCC tissues, and high AFAP1-AS1 expression was associated with tumor size, TNM stage, vascular invasion, and poor prognosis. Silencing of AFAP1-AS1 significantly reduced cell proliferation, clonal growth, cell migration, and invasion and increased apoptosis in vitro. Furthermore, AFAP1-AS1 silencing markedly reduced tumor growth in a murine allograft model in vivo. The results suggested that AFAP1-AS1 is important in HCC development and serves as a therapeutic target of HCC.

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Both transforming growth factor-beta (TGF-β) and lipopolysaccharide (LPS) can activate hepatic stellate cells (HSCs), thus increasing expressions of alpha smooth muscle actin (α-SMA) and type I collagen alpha 1 (Col1α1) and promoting liver fibrosis. However, whether TGF-β and LPS have a common downstream reactor remains unclear. Recently, a strong relationship of circular RNAs (circRNAs) and fibrogenesis has been elucidated. In this study, we compared the expressions of several circRNAs in TGF-β- and LPS-activated HSCs, and found that circ-PWWP2A was upregulated in both TGF-β- and LPS-activated HSCs and in mouse fibrotic liver tissues. Meanwhile, circ-PWWP2A was positively correlated with HSC activation and proliferation. Two microRNAs, miR-203 and miR-223, were identified to be the downstream targets of circ-PWWP2A using luciferase reporter assay and pull-down interaction assay. Circ-PWWP2A was suggested to promote HSC activation and proliferation via sponging miR-203 and miR-223, and subsequently increasing Fstl1 and TLR4, respectively. Furthermore, downregulating circ-PWWP2A was indicated to alleviate hepatic fibrosis in vivo. In conclusion, our findings indicated that circ-PWWP2A is the common downstream reactor of TGF-β and LPS in HSC activation, and that circ-PWWP2A plays a critical role in hepatic fibrogenesis via sponging miR-203 and miR-223.