N6-methyladenosine modification promotes hepatocarcinogenesis through circ-CDYL-enriched and EpCAM-positive liver tumor-initiating exosomes.

CircRNAs play multiple roles in a variety of cellular processes. We found that Circ-CDYL is highly enriched in early HCC plasma exosomes. Moreover, EpCAM+ HCC cells and exosomes had significant Circ-CDYL levels. We postulated that Circ-CDYL-enriched and EpCAM-positive exosomes would function as liver tumor-initiating exosomes (LTi-Exos). As predicted, intercellular transfer of LTi-Exos activates the HDGF-PI3K-AKT-mTOR and HIF1AN-NOTCH2 axes in recipient cells, promoting malignancy. Upstream, we found that the N6-methyladenosine (m6A) modification of Circ-CDYL exerted its action in HCC cells through a dual mechanism. First, it stimulated back-splicing processes via YTHDC1 to promote Circ-CDYL biogenesis. Second, it facilitates the active sorting of Circ-CDYL into exosomes via hnRNPA2/B1. Clinically, the combination of LTi-Exos and plasma alpha-fetoprotein (AFP) provides a promising early diagnostic biomarker for HCC with an AUC of 0.896. This study highlights the effect and mechanism by which m6A modification promotes hepatocarcinogenesis via modulation of the tumor microenvironment by LTi-Exos.

The Comparison of Surgical Margins and Type of Hepatic Resection for Hepatocellular Carcinoma With Microvascular Invasion.

OBJECTIVE: The objective of this study was to investigate the impact of surgical margin and hepatic resection on prognosis and compare their importance on prognosis in patients with hepatocellular carcinoma (HCC). METHODS: The clinical data of 906 patients with HCC who underwent hepatic resection in our hospital from January 2013 to January 2015 were collected retrospectively. All patients were divided into anatomical resection (AR) (n = 234) and nonanatomical resection (NAR) group (n = 672) according to type of hepatic resection. The effects of AR and NAR and wide and narrow margins on overall survival (OS) and time to recurrence (TTR) were analyzed. RESULTS: In all patients, narrow margin (1.560, 1.278-1.904; 1.387, 1.174-1.639) is an independent risk factor for OS and TTR, and NAR is not. Subgroup analysis showed that narrow margins (2.307, 1.699-3.132; 1.884, 1.439-2.468), and NAR (1.481, 1.047-2.095; 1.372, 1.012-1.860) are independent risk factors for OS and TTR in patients with microvascular invasion (MVI)-positive. Further analysis showed that for patients with MVI-positive HCC, NAR with wide margins was a protective factor for OS and TTR compared to AR with narrow margins (0.618, 0.396-0.965; 0.662, 0.448-0.978). The 1, 3, and 5 years OS and TTR rate of the two group were 81%, 49%, 29% versus 89%, 64%, 49% (P = .008) and 42%, 79%, 89% versus 32%, 58%, 74% (P = .024), respectively. CONCLUSIONS: For patients with MVI-positive HCC, AR and wide margins were protective factors for prognosis. However, wide margins are more important than AR on prognosis. In the clinical setting, if the wide margins and AR cannot be ensured at the same time, the wide margins should be ensured first.

FoxR2 promotes glioma proliferation by suppression of the p27 pathway.

FoxR2 plays an important role in the development of many human tumors. However, the effects of FoxR2 on tumorigenicity of human glioma remain unclear. In this study, we investigated the roles of FoxR2 in cell proliferation and invasion of glioma. We found that overexpression of FoxR2 promoted the proliferation, migration and invasion of glioma cells. Knockout of FoxR2 induced G1 arrest by decreasing the expression levels of cyclin D1, cyclin E and p-Rb. Mechanistically, upregulation of FoxR2 increased the level and activity of MMP-2 and decreased the expression of p27. Furthermore, overexpression of FoxR2 decreased the nuclear accumulation of p27. Taken together, these results indicate that upregulation of FoxR2 may confer enhanced tumorigenicity in glioma cells.