Yuli Jia

Long non-coding RNA TUSC7 acts a molecular sponge for miR-10a and suppresses EMT in hepatocellular carcinoma

Despite advances in the roles of long non-coding RNA (lncRNA) tumor suppressor candidate 7 (TUSC7) in cancer biology, which has been identified as a tumor suppressor by regulating cell proliferation, apoptosis, migration, invasion, cell cycle, and tumor growth, the function of TUSC7 in hepatocellular carcinoma (HCC) remains unknown. In this study, we observed that the expression of TUSC7 was immensely decreased in HCC. Clinically, the lower expression of TUSC7 predicted poorer survival and may be an independent risk factor for HCC patients. Moreover, TUSC7 inhibited cell metastasis, invasion, and epithelial-to-mesenchymal transformation (EMT) through competitively binding miR-10a. Furthermore, we found that TUSC7 could decrease the expression of Eph tyrosine kinase receptor A4 (EphA4), a downstream target of miR-10a as well as an EMT suppressor, through TUSC7-miR-10a-EphA4 axis. Taken together, we demonstrate that TUSC7 suppresses EMT through the TUSC7-miR-10a-EphA4 axis, which may be a potential target for therapeutic intervention in HCC.

Ftx non coding RNA-derived miR-545 promotes cell proliferation by targeting RIG-I in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. Accumulating studies have demonstrated that aberrant expression of several lncRNAs was found to be involved in the hepatocarcinogenesis. In this study, a lncRNA Ftx was chosen to investigate its effects on HCC cells, and clarify the possible mechanism. We demonstrated that the lncRNA Ftx and Ftx-derived miR-545 were up-regulated in both HCC tissues and cells. MiR-545 was positively correlated with lncRNA Ftx expression. Notably, clinical association analysis revealed that the high expression of lncRNA Ftx and miR-545 was associated with poor prognostic features, and conferred a reduced 5-year overall survival (OS) and disease-free survival (DFS) of HCC patients. We found that miR-545 was a pivotal mediator in Ftx-induced promotion of HCC cell growth. Subsequently, we identified RIG-I as a direct target of miR-545. The expression of RIG-I was downregulated in HCC tissues and was inversely correlated with miR-545 expression. Our data revealed that ectopic expression of RIG-I abrogated the effects of lncRNA Ftx or miR-545 on HCC cells. LncRNA Ftx/miR-545-mediated downregulation of RIG-I led to increased Akt phosphorylation in vitro and in vivo. Inhibition of Akt phosphorylation abolished the effects of lncRNA Ftx/miR-545 on HCC cells. In conclusion, our study demonstrates that the novel pathway lncRNA Ftx/miR-545/RIG-I promotes HCC development by activating PI3K/Akt signaling, and it may serve as a novel prognostic biomarker and therapeutic target for HCC.

Methylation-mediated repression of microRNA-129-2 suppresses cell aggressiveness by inhibiting high mobility group box 1 in human hepatocellular carcinoma

Aberrant expression of microRNAs (miRNAs) and its dysfunction have been revealed as crucial modulators of cancer initiation and progression. MiR-129-2 has been reported to play a tumor suppressive role in different human malignancies. Here, we demonstrated that miR-129-2 was significantly decreased in hepatocellular carcinoma (HCC) tissues and cell lines. Furthermore, miR-129-2 was expressed at significant lower levels in aggressive and recurrent tumor tissues. Clinical analysis indicated that miR-129-2 expression was inversely correlated with venous infiltration, high Edmondson-Steiner grading and advanced tumor-node-metastasis (TNM) stage in HCC. Notably, miR-129-2 was an independent prognostic factor for indicating overall survival (OS) and disease-free survival (DFS) of HCC patients. Ectopic expression of miR-129-2 inhibited cell migration and invasion in vitro and in vivo. Furthermore, we confirmed that high mobility group box 1 (HMGB1) was a direct target of miR-129-2, and it abrogated the function of miR-129-2 in HCC. Mechanistic investigations showed that miR-129-2 overexpression inhibited AKT phosphorylation at Ser473 and decreased the expression of matrix metalloproteinase2/9 (MMP2/9). Upregulation of p-AKT abolished the decreased cell migration and invasion induced by miR-129-2 in HCC. Whereas inhibition of Akt phosphorylation significantly decreased HMGB1-enhanced HCC cell migration and invasion. Moreover, we found that miR-129-2 was downregulated by DNA methylation, and demethylation of miR-129-2 increased miR-129-2 expression in HCC cells and resulted in significant inhibitory effects on cell migration and invasion. In conclusion, miR-129-2 may serve as a prognostic indicator for HCC patients and exerts tumor suppressive role, at least in part, by inhibiting HMGB1.

miR-187-3p inhibits the metastasis and epithelial–mesenchymal transition of hepatocellular carcinoma by targeting S100A4

miR-187-3p, a novel cancer-related microRNA, was previously reported to play promoting or suppressive roles in different malignancies. However, the expression level, biological function, and underlying mechanisms of miR-187-3p in hepatocellular carcinoma (HCC) remain unknown. This study demonstrated that miR-187-3p was significantly down-regulated in HCC tissues and cell lines, and was associated with advanced TNM stage and metastasis in HCC. Functional studies confirmed that miR-187-3p could inhibit the metastasis of HCC both in vitro and in vivo. Moreover, we proved that miR-187-3p could prevent the epithelial-mesenchymal transition (EMT) of HCC cells. Mechanically, S100A4 was a direct downstream target of miR-187-3p, and mediated the functional influence of miR-187-3p in HCC. Furthermore, miR-187-3p and S100A4 expression was evidently correlated with adverse clinical features and poor prognosis of HCC. Lastly, we showed that hypoxia was responsible for the significantly decreased level of miR-187-3p in HCC, and miR-187-3p was involved in the promoting effects of hypoxia on the metastasis and EMT of HCC cells. Taken together, miR-187-3p inhibits the metastasis and EMT in HCC by targeting S100A4. miR-187-3p can serve as a prognostic indicator and a promising therapeutic target for HCC patients.

Systematic review and meta-analysis of prophylactic abdominal drainage after pancreatic resection

AIM To investigate whether prophylactic abdominal drainage is necessary after pancreatic resection. METHODS PubMed, Web of Science, and the Cochrane Library were systematically searched to obtain relevant articles published before January 2014. Publications were retrieved if they met the selection criteria. The outcomes of interest included: mortality, morbidity, postoperative pancreatic fistula (POPF), clinically relevant pancreatic fistula (CR-PF), abdominal abscess, reoperation rate, the rate of interventional radiology drainage, and the length of hospital stay. Subgroup analyses were also performed for pancreaticoduodenectomy (PD) and for distal pancreatectomy. Beggs funnel plot and the Egger regression test were employed to assess potential publication bias. RESULTS Nine eligible studies involving a total of 2794 patients were identified and included in this meta-analysis. Of the included patients, 1373 received prophylactic abdominal drainage. A fixed-effects model meta-analysis showed that placement of prophylactic drainage did not have beneficial effects on clinical outcomes, including morbidity, POPF, CR-PF, reoperation, interventional radiology drainage, and length of hospital stay (Ps > 0.05). In addition, prophylactic drainage did not significantly increase the risk of abdominal abscess. Overall analysis showed that omitting prophylactic abdominal drainage resulted in higher mortality after pancreatectomy (OR = 1.56; 95%CI: 0.93-2.92). Subgroup analysis of PD showed similar results to those in the overall analysis. Elimination of prophylactic abdominal drainage after PD led to a significant increase in mortality (OR = 2.39; 95%CI: 1.22-4.69; P = 0.01). CONCLUSION Prophylactic abdominal drainage after pancreatic resection is still necessary, though more evidence from randomized controlled trials assessing prophylactic drainage after PD and distal pancreatectomy are needed.

IL-6/STAT3 axis initiated CAFs via up-regulating TIMP-1 which was attenuated by acetylation of STAT3 induced by PCAF in HCC microenvironment.

Aberrant tumor microenvironment is involved closely in tumor initiation and progression, in which cancer associated fibroblasts (CAFs) play a pivotal role. Both IL-6/STAT3 signaling and TIMP-1 have been found to modulate the crosstalk between tumor cells and CAFs in tumor microenvironment, however, the underlying mechanism remains unclear. Here, we showed that IL-6/STAT3 signaling was activated aberrantly in HCC tissues and correlated with poor post-surgical outcome. The in vitro experiments confirmed that activation of IL-6/STAT3 pathway enhanced TIMP-1 expression directly via phosphorylated STATs (p-STAT3)-binding with TIMP-1 promoter in Huh7 cells. Furthermore, activation of IL-6/STAT3 pathway in HCC cells was shown to induce the transformation from normal liver fibroblasts (LFs) to CAFs via up-regulating TIMP-1 expression. Co-culture with CAFs promoted the growth of Huh7 cells both in vitro and in vivo. Finally, by co-Immunoprecipitation and immunoblotting assessments, PCAF, a well-known acetyltransferase, was revealed to acetylate cytoplasmic STAT3 protein directly and regulate TIMP-1 expression negatively in Huh7 cells. In summary, this investigation indicated that there was a positive IL-6/TIMP-1 feedback loop controlling the crosstalk between HCC cells and its neighbouring fibroblasts. The data here also identified that PCAF repressed TIMP-1 expression via acetylation of STAT3. In conclusion, this investigation demonstrated that CAFs promoted HCC growth via IL-6/STAT3/AKT pathway and TIMP-1 over-expression driven by IL-6/STAT3 pathway in HCC cells brought in more CAFs through activating LFs. Finally, PCAF could block this positive feedback by acetylating STAT3 in HCC cells.

PCAF inhibits hepatocellular carcinoma metastasis by inhibition of epithelial-mesenchymal transition by targeting Gli-1

UNLABELLED The p300-CBP-associated factor (PCAF), other than its histone acetyltransferase (HAT) activity, possesses an intrinsic ubiquitination activity that is involved in various transcriptional regulators, including the transcription factor glioma-associated oncogene 1 (Gli1), a well-known regulator of epithelial-mesenchymal transition (EMT) in cancer. In present research, we detected that PCAF was down-regulated in hepatocellular carcinoma (HCC) tissues compared with the adjacent non-tumor tissues and significantly associated with malignant portal vein invasion (p < 0.05) and poor survival (p < 0.05) of HCC patients. Moreover, functional study demonstrated that downregulation of PCAF facilitated tumor cell migration, invasion via EMT. Further study found that Gli1 as a direct target of PCAF induced EMT and promoted tumor metastasis and invasion. CONCLUSION PCAF is an anti-oncogene that plays an important role in the development of HCC by suppressing HCC cell metastasis and EMT by targeting Gli1, which indicates the potential therapeutic value of PCAF for suppression of metastasis of HCC.

P300/CBP-associated factor (PCAF) inhibits the growth of hepatocellular carcinoma by promoting cell autophagy.

Aberrant autophagic processes have been found to have fundamental roles in the pathogenesis of different kinds of tumors, including hepatocellular carcinoma (HCC). P300/CBP-associated factor (PCAF), a histone acetyltransferase (HAT), performs its function by acetylating both histone and non-histone proteins. Our previous studies showed that PCAF was downregulated in HCC tissues and its high expression was significantly associated with patient survival after surgery, serving as a prognostic marker. In this study we found that overexpression of PCAF induced autophagy of HCC cells and its knockdown depressed autophagy. As type II programmed cell death, autophagy induced by PCAF-elicited cell death in HCC cells. In vivo experiments confirmed that PCAF-induced autophagy inhibited tumor growth. Subsequent in vitro experiments showed that PCAF promoted autophagy by inhibiting Akt/mTOR signaling pathway. Our findings show that PCAF is a novel modulator of autophagy in HCC, and can serve as an attractive therapeutic strategy of HCC treatment.

High‑mobility group box 1 has a prognostic role and contributes to epithelial mesenchymal transition in human hepatocellular carcinoma

High‑mobility group box 1 (HMGB1), a member of the high‑mobility group protein family, was originally characterized as a non‑histone, nuclear DNA‑binding protein. While the roles of HMGB1 in inflammation and cell differentiation have been previously reported, its role in tumor cell migration and invasion, particularly in hepatocellular carcinoma (HCC), has remained elusive. The present study reported that the expression of HMGB1 in HCC tissues was significantly higher than that in matched tumor‑adjacent tissues (P<0.05). HMGB1 was expressed at significantly elevated levels in tumors of patients with large tumor size, high histological grade and advanced tumor‑node‑metastasis stage (P<0.05). The positive expression of HMGB1 correlated with a poor three‑year overall and disease‑free survival of HCC patients (P<0.05). In addition, HMGB1 was an independent factor for predicting the three‑year overall and disease‑free survival of HCC patients (P<0.05). An in vitro experiment revealed that knockdown of HMGB1 inhibited cell migration and invasion in the HCC cell lines Huh7 and MHCC97H (P<0.05). Furthermore, western blot analysis showed that HMGB1 knockdown markedly inhibited epithelial mesenchymal transition in Huh7 and MHCC97H cells. These results suggested that HMGB1 may be utilized as an independent prognostic marker in HCC and may promote tumor progression by promoting cell migration and invasion.

BCAT1 promotes tumor cell migration and invasion in hepatocellular carcinoma

Branched-chain amino acid transaminase 1 (BCAT1) has been associated with numerous types of tumors; however, few previous studies have evaluated the expression and role of BCAT1 in hepatocellular carcinoma (HCC). In the present study, the expression of BCAT1 was detected by reverse transcription-quantitative polymerase chain reaction and immunoblotting in six HCC cell lines and 74 pairs of HCC and adjacent non-cancerous liver tissues. In addition, the correlation between the expression levels of c-Myc and BCAT1 was analyzed using immunohistochemistry. Furthermore, RNA silencing was performed using c-Myc-specific or BCAT1-specific small interfering RNA, after which wound healing and Transwell cell invasion assays were performed. Finally, the clinicopathological characteristics of BCAT1 in patients with HCC were analyzed. It was shown that the expression of BCAT1 was significantly higher in HCC tissues compared with adjacent non-tumor tissues (P<0.001), and in HCC cell lines compared within the L-02 hepatic cell line (P<0.001). In addition, immunohistochemical analyses indicated that the expression of BCAT1 was positively correlated with c-Myc (r=0.706, P<0.001). BCAT1 expression was shown to be downregulated in c-Myc-knockdown cells, and silencing of BCAT1 expression reduced the invasion and migration of HCC cells. Furthermore, a clinical analysis indicated that BCAT1 expression in HCC tissues was significantly associated with the tumor-node-metastasis stage, tumor number and tumor differentiation (all P<0.05), and that BCAT1 was able to predict the 5-year survival and disease-free survival rates of patients with HCC (both P<0.001). The results of the present study suggested that BCAT1 expression is upregulated in patients with HCC, and that BCAT1 may serve as a potential molecular target for the diagnosis and treatment of HCC.