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Early and late recurrences of solitary HCC after curative resection are associated with different predictive factors. The time to recurrence and further curative treatment after recurrence were the best predictors of survival post recurrence.

Hepatocellular carcinoma (HCC) is one of the fastest‐rising causes of cancer‐related death worldwide, but its deficiency of specific biomarkers and therapeutic targets in the early stages lead to severe inadequacy in the early diagnosis and treatment of HCC. Covalently closed circular RNA (circRNA), which was once considered an aberrant splicing by‐product, is now drawing new interest in cancer research because of its remarkable functionality. Beneath the surface of the dominant functional proteins events, a hidden circRNA‐centric noncoding regulatory RNAs network active in the very early stage of HCC is here revealed by a genome‐wide analysis of mRNA, circRNA, and microRNA (miRNA) expression profiles. Circ‐CDYL (chromodomain Y like) is specifically up‐regulated in the early stages of HCC and therefore contributes to the properties of epithelial cell adhesion molecule (EPCAM)‐positive liver tumor‐initiating cells. Circ‐CDYL interacts with mRNAs encoding hepatoma‐derived growth factor (HDGF) and hypoxia‐inducible factor asparagine hydroxylase (HIF1AN) by acting as the sponge of miR‐892a and miR‐328‐3p, respectively. Subsequently, activation of the phosphoinositide 3‐kinase (PI3K)‐AKT serine/threonine kinase‐mechanistic target of rapamycin kinase complex 1/β‐catenin and NOTCH2 pathways, which promote the expression of the effect proteins, baculoviral IAP repeat containing 5 (BIRC5 or SURVIVIN) and MYC proto‐oncogene, is influenced by circ‐CDYL. A treatment incorporating circ‐CDYL interference and traditional enzyme inhibitors targeting PI3K and HIF1AN demonstrated highly effective inhibition of stem‐like characteristics and tumor growth in HCC. Finally, we demonstrated that circ‐CDYL expression or which combined with HDGF and HIF1AN are both independent markers for discrimination of early stages of HCC with the odds ratios of 1.09 (95% confidence interval [CI], 1.02‐1.17) and 124.58 (95% CI, 13.26‐1170.56), respectively. Conclusion: These findings uncover a circRNA‐centric noncoding regulatory RNAs network in the early stages of HCC and thus provide a possibility for surveillance and early treatment of HCC.

Current chemotherapeutic and butyrate therapeutics that induce fetal hemoglobin expression generally also suppress erythropoiesis, limiting the production of cells containing fetal hemoglobin (F cells). Recently, selected short-chain fatty acid derivatives (SCFADs) were identified that induce endogenous ␥-globin expression in K562 cells and human burst-forming units-erythroid and that increase proliferation of human erythroid progenitors and a multilineage interleukin-3-dependent hematopoietic cell line. In this report, ␥-globin inducibility by these SCFADs was further demonstrated in mice transgenic for the locus control region and the entire ␤-globin gene locus in a yeast artificial chromosome and in 2 globin promoter-reporter assays. Conditioned media experiments strongly suggest that their proliferative activity is a direct effect of the test compounds. Investigation of potential mechanisms of action of these SCFADs demonstrates that these compounds induce prolonged expression of the growth-promoting genes c-myb and c-myc. Both butyrate and specific growth-stimulatory SCFADs induced prolonged signal transducer and activator of transcription (STAT)-5 phosphorylation and activation, and c-cis expression, persisting for more than 120 minutes, whereas with IL-3 alone phosphorylation disappeared within minutes. In contrast to butyrate treatment, the growth-stimulating SCFADs did not result in bulk histone H4 hyperacetylation or induction of p21 Waf/Cip , which mediates the suppression of cellular growth by butyrate. These findings suggest that the absence of bulk histone hyperacetylation and p21 induction, but prolonged induction of cis, myb, myc, and IntroductionButyrate analogs have been of interest as potential therapeutics for the ␤-globin disorders following the demonstration that butyrate could transcriptionally activate developmentally silenced fetal and embryonic globin genes in many experimental conditions. [1][2][3][4][5][6][7][8][9][10][11] In clinical trials, arginine butyrate stimulated hemoglobin F (HbF) synthesis to levels above 20% and induced a nearly 2-fold increase in the amount of HbF/cell and in proportions of red blood cells expressing HbF (F reticulocytes) in patients with sickle cell anemia. [10][11][12] With constant use, however, the activity of the drug in maintaining substantial increases in HbF-containing erythrocytes gradually decreased. 13 We hypothesized that this tachyphylaxis was due to the coincident cellular growth-inhibitory properties of butyrate and developed intermittent or "pulse" regimens (4 days of use per month) to surmount this problem. 12 Although this regimen proved effective, it also imposed severe limitations on the amount of drug that can be delivered to the patient. An orally bioavailable transcriptional inducer of ␥-globin that does not have cellular growth-inhibitory properties and could be administered more frequently to stimulate a further increase in the proportion of HbF-containing cells (F cells) would be therapeutically advantageous for ␤-globin disord...

Epigenetic modification of miR-429 can manipulate liver T-ICs by targeting the RBBP4/E2F1/OCT4 axis. This miRNA might be targeted to inactivate T-ICs, thus providing a novel strategy for HCC prevention and treatment.

BackgroundPreoperative jaundice is frequent in gallbladder cancer (GBC) and indicates advanced disease. Resection is rarely recommended to treat advanced GBC. An aggressive surgical approach for advanced GBC remains lacking because of the association of this disease with serious postoperative complications and poor prognosis. This study aims to re-assess the prognostic value of jaundice for the morbidity, mortality, and survival of GBC patients who underwent surgical resection with curative intent.MethodsGBC patients who underwent surgical resection with curative intent at a single institution between January 2003 and December 2012 were identified from a prospectively maintained database.ResultsA total of 192 patients underwent surgical resection with curative intent, of whom 47 had preoperative jaundice and 145 had none. Compared with the non-jaundiced patients, the jaundiced patients had significantly longer operative time (p < 0.001) and more intra-operative bleeding (p = 0.001), frequent combined resections of adjacent organs (23.4% vs. 2.8%, p = 0.001), and postoperative complications (12.4% vs. 34%, p = 0.001). Multivariate analysis showed that preoperative jaundice was the only independent predictor of postoperative complications. The jaundiced patients had lower survival rates than the non-jaundiced patients (p < 0.001). However, lymph node metastasis and gallbladder neck tumors were the only significant risk factors of poor prognosis. Non-curative resection was the only independent predictor of poor prognosis among the jaundiced patients. The survival rates of the jaundiced patients with preoperative biliary drainage (PBD) were similar to those of the jaundiced patients without PBD (p = 0.968). No significant differences in the rate of postoperative intra-abdominal abscesses were found between the jaundiced patients with and without PBD (n = 4, 21.1% vs. n = 5, 17.9%, p = 0.787).ConclusionsPreoperative jaundice indicates poor prognosis and high postoperative morbidity but is not a surgical contraindication. Gallbladder neck tumors significantly increase the surgical difficulty and reduce the opportunities for radical resection. Gallbladder neck tumors can independently predict poor outcome. PBD correlates with neither a low rate of postoperative intra-abdominal abscesses nor a high survival rate.

Germ line mutations of the ubiquitin ligase cullin 7 (CUL7) are linked to 3-M syndrome and Yakuts short stature syndrome, both of which are characterized by pre-and post-natal growth retardation. CUL7 knock-out mice show placental and embryonic defects similar to intrauterine growth retardation, suggesting a role of CUL7 in placentation. CUL7 was found in this study to be highly expressed in first trimester invasive human placental villi as well as in HTR8/SVneo and B6Tert cells, two cell lines derived from human first trimester trophoblast cells. However, CUL7 levels in term trophoblast cells or JEG-3 cells, which are derived from human choriocarcinoma but exhibit weak invasion capacity, were low or undetectable. Forced expression of CUL7 in JEG-3 cells induced cell morphological changes characteristic of epithelial-mesenchymal transition, which was accompanied by a complete loss of the epithelial markers E-cadherin and P-cadherin and a significant elevation of mesenchymal markers Vimentin and N-cadherin. JEG-3 cells expressing CUL7 exhibited enhanced cell migration and invasion. Conversely, CUL7-specific RNA interference in HTR8/SVneo cells resulted in increased E-cadherin expression and reduced cell migration and invasion. Furthermore, CUL7 expression downregulated E-cadherin mRNA expression by up-regulating ZEB1 and Slug, two transcriptional repressors of E-cadherin. Finally, CUL7-induced loss of E-cadherin expression was partially reversed by treatment of CUL7-expressing cells with the proteasome inhibitor MG-132. These results suggest that the CUL7 E3 ligase is a key regulator in trophoblast cell epithelial-mesenchymal transition and placental development.

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