PurposeStudies show that high expression of non-SMC condensin I complex subunit G (NCAPG) is associated with many tumors. In this study, we explore the mechanism by which NCAPG promotes proliferation in hepatocellular carcinoma (HCC).Patients and methodsLiver cancer and paracancerous tissue specimens of 90 HCC patients were collected, and expression levels of NCAPG in these tissues and cell lines were evaluated by Western blotting and immunohistochemistry. HCC cells were transfected with siRNAs and plasmids, and pathway activators or inhibitors were added. The 5-ethynyl-2ʹ-deoxyuridine (EdU) proliferation assay was used to measure cell proliferation. Flow cytometry was used to evaluate cell apoptosis. Western blot assays were performed as a standard procedure to detect total protein expression. Treated HCC cells were subcutaneously injected into nude mice.ResultsAnalysis using the Oncomine database showed that NCAPG was upregulated in HCC and immunohistochemistry and Western blot assays showed it was upregulated in both HCC tissues and HCC cell lines. The overexpression of NCAPG could promote HCC cell proliferation and reduce HCC cell apoptosis. More importantly, RNA-sequencing analysis predicted that NCAPG plays a role in the HCC via PI3K-AKT signaling pathway. The PI3K/AKT/FOXO4 pathway was aberrantly activated, and the expressions of apoptosis-related protein were altered when NCAPG was overexpressed or silenced both in vitro and in vivo. LY294002, a PI3K inhibitor, could eliminate the NCAPG role of promoting HCC cell proliferation and reducing HCC cell apoptosis, while 740Y-P, a PI3K activator, contributed to the opposite effect.ConclusionNCAPG functions as an oncogene in HCC and plays a role in promoting cell proliferation and antiapoptosis through activating the PI3K/AKT/FOXO4 pathway.

Interferon‐induced transmembrane protein 3 (IFITM3) has been shown to be overexpressed in multiple cancers. However, the role of IFITM3 in metastasis of hepatocellular carcinoma (HCC) is still poorly understood. In this study, we showed that IFITM3 was frequently overexpressed in HCC tissues compared with adjacent nontumor tissues. Overexpression of IFITM3 was significantly correlated with tumor metastasis and poor prognosis in HCC. Knockdown of IFITM3 dramatically decreased MMP9 expression and inhibited the invasion and metastasis of HCC in vitro and in vivo . Moreover, the upregulation of MMP9 rescued the decreased migration and invasion induced by the knockdown of IFITM3, whereas the knockdown of MMP9 decreased IFITM3‐enhanced HCC migration and invasion. Mechanistically, we found that IFITM3 regulates MMP9 expression through the p38/MAPK pathway. Taken together, we identified a novel IFITM3–p38/MAPK–MMP9 regulatory circuitry, the dysfunction of which drives invasive and metastatic character in HCC.

The interferon-induced transmembrane protein 3 (IFITM3, also called 1-8U) gene represents dysregulated expression in various tumors and is involved in tumorigenesis and progression. However, the role of IFITM3 and its underlying mechanism in hepatocellular carcinoma (HCC) are still far from elucidated. MicroRNAs (miRNAs), a class of endogenous (approximately 22 nucleotides) small noncoding RNAs, can post-transcriptionally regulate gene expression by repressing protein translation or silencing the expression of target genes that play critical roles in various cancers. miR-29a was identified as being aberrantly expressed in a significant proportion of HCC. However, the correlation between IFITM3 and miR-29a has not been reported to date. In this study, we investigated the expression of IFITM3 in HCC and its effect on the biological behavior of HCC cells as well as the association between IFITM3 and miR-29a. We determined that IFITM3 was upregulated and miR-29a downregulated in HCC tissues and that they were associated with HCC tumor size, tumor multifocal, and venous invasion. The expression of IFITM3 in HCC tissues was negatively correlated with miR-29a expression. Additionally, IFITM3 overexpression and miR-29a nonoverexpression were related to poor prognosis of HCC patients. Knockdown of IFITM3 inhibited migration, invasion, proliferation and promoted apoptosis of HCC cells, which are consistent with the effects of upregulated miR-29a. Additionally, after upregulation of IFITM3, the invasion, migration and proliferation abilities of HL-7702 cells were increased, but the apoptosis rate was decreased. Furthermore, using a Dual-Luciferase reporter gene assay, we identified IFITM3 as a new functional target gene of miR-29a. In conclusion, our findings demonstrated that the migration, invasion, proliferation and apoptosis features of HCC cells could be regulated by miR-29a via IFITM3. Thus, the present study indicated that miR-29a and IFITM3 play critical roles in the development and progression of HCC, revealing that miR-29a and IFITM3 may be novel potential therapeutic targets for patients with HCC.

Purpose: Numerous studies have shown that the expression of microRNA-181c (miR-181c) is inhibited in various cancers, which suggests that it has a cancer suppressive effect. In the current study, we evaluated the regulation and characteristics of miR-181c in human hepatocellular carcinoma (HCC). Materials and methods: Samples of tumor tissues and adjacent non-tumor tissues were collected from 52 patients with HCC, and expression levels of miR-181c in these samples were investigated via quantitative real-time polymerase chain reaction. HCC cell migration and invasion were investigated via wound healing assays and transwell assays. HCC cell apoptosis rates were assessed via flow cytometry, and HCC proliferation was assessed via 5-ethynyl-20-deoxyuridine assays. In vivo tumors were initiated by subcutaneously inoculating HCC cells into nude mice. And various biomarkers were investigated via western blotting. Results: In microarray datasets and tumor tissues, significant downregulation of miR-181c was apparent compared with non-tumorous adjacent tissues. Expression of miR-181c in HCC cells was also significantly lower than it was in normal human liver cells. miR-181c regulated the migration, invasion, apoptosis, and proliferation of HCC cell lines in vitro, and tumor development in vivo. Observations also suggest that miR-181c regulates NCAPG in HCC cells, and its expression affects cellular invasion, migration, proliferation, and apoptosis. There was a negative correlation between miR-181c expression and NCAPG in HCC tissue samples. Conclusion: miR-181c exhibits tumor-suppression via the regulation of NCAPG levels.

Idiopathic pulmonary arterial hypertension (IPAH) is a rare vascular disease with a poor prognosis, and the mechanism of its development remains unclear. Further molecular pathology studies may contribute to a comprehensive understanding of IPAH and provide new insights into diagnostic markers and potential therapeutic targets. Iron deficiency has been reported in 43-63% of patients with IPAH and is associated with reduced exercise capacity and higher mortality, suggesting that dysregulated iron metabolism may play an unrecognized role in influencing the development of IPAH. In this study, we explored the regulatory mechanisms of iron metabolism in IPAH by bioinformatic analysis. The molecular function of iron metabolism-related genes (IMRGs) is mainly enriched in active transmembrane transporter activity, and they mainly affect the biological process of response to oxidative stress. Ferroptosis and fluid shear stress and atherosclerosis pathways may be the critical pathways regulating iron metabolism in IPAH. We further identified 7 key genes (BCL2, GCLM, MSMO1, SLC7A11, SRXN1, TSPAN5, and TXNRD1) and 5 of the key genes (BCL2, MSMO1, SLC7A11, TSPAN5, and TXNRD1) as target genes may be regulated by 6 dysregulated miRNAs (miR-483-5p, miR-27a-3p, miR-27b-3p, miR-26b-5p, miR-199a-5p, and miR-23b-3p) in IPAH. In addition, we predicted potential IPAH drugs—celastrol and cinnamaldehyde—that target iron metabolism based on our results. These results provide insights for further definition of the role of dysregulated iron metabolism in IPAH and contribute to a deeper understanding of the molecular mechanisms and potential therapeutic targets of IPAH.