LncRNA ZFAS1 regulates ATIC transcription and promotes the proliferation and migration of hepatocellular carcinoma through the PI3K/AKT signaling pathway.

PURPOSE: Long noncoding RNAs (lncRNAs) exert a significant influence on various cancer-related processes through their intricate interactions with RNAs. Among these, lncRNA ZFAS1 has been implicated in oncogenic roles in multiple cancer types. Nevertheless, the intricate biological significance and underlying mechanism of ZFAS1 in the initiation and progression of hepatocellular carcinoma (HCC) remain largely unexplored. METHODS: Analysis of The Cancer Genome Atlas Program (TCGA) database revealed a notable upregulation of lncRNA ZFAS1 in HCC tissues. To explore its function, we investigated colony formation and performed CCK-8 assays to gauge cellular proliferation and wound healing, Transwell assays to assess cellular migration, and an in vivo study employing a nude mouse model to scrutinize tumor growth and metastasis. Luciferase reporter assay was used to confirm the implicated interactions. Rescue experiments were conducted to unravel the plausible mechanism underlying the activation of the PI3K/AKT pathway by lncRNAs ZFAS1 and ATIC. RESULTS: ZFAS1 and ATIC were significantly upregulated in the HCC tissues and cells. ZFAS1 knockdown inhibited cell proliferation and migration. We observed a direct interaction between the lncRNA ZFAS1 and ATIC. ATIC knockdown also suppressed cell proliferation and migration. SC79, an activator of AKT, partially restores the effects of lncRNA ZFAS1/ATIC knockdown on cell proliferation and migration. Knockdown of lncRNA ZFAS1/ATIC inhibited tumor growth and lung metastasis in vivo. CONCLUSION: Overall, lncRNA ZFAS1 regulates ATIC transcription and contributes to the growth and migration of HCC cells through the PI3K/AKT signaling pathway.

miR-33a-3p regulates METTL3-mediated AREG stability and alters EMT to inhibit pancreatic cancer invasion and metastasis.

Recent studies have shown that amphoteric regulatory protein (AREG), a member of the epidermal growth factor (EGF) family, is expressed in many cancers and is an independent prognostic indicator for patients with pancreatic cancer, but whether AREG is regulated at the epigenetic level to promote the development of pancreatic cancer (PC) has not been elucidated. Our results support the notion that AREG is overexpressed in pancreatic cancer tissues and cell lines. Functionally, the deletion of AREG impedes pancreatic cancer (PC) cell proliferation, migration, and invasion. In addition, we identified and validated that methyltransferase-like 3 (METTL3) induced the m6A modification on AREG and facilitated the stability of AREG mRNA after sequencing. Additionally, we obtained experimental evidence that miR-33a-3p targets and inhibits METTL3 from taking action, as predicted by using the miRDB and RNAinter. Remediation experiments showed that miR-33a-3p inhibits PC progression through METTL3. In summary, this research reveals that miR-33a-3p inhibits m6A-induced stabilization of AREG by targeting METTL3, which plays a key role in the aggressive progression of PC. AREG could be a potential target for PC treatment.

A novel difficulty scoring system of laparoscopic liver resection for liver tumor.

Objectives: To develop a novel difficulty scoring system (NDSS) to predict the surgical difficulty of laparoscopic hepatectomy. Patients and methods: A total of 138 patients with liver tumors performed liver resection (LLR) between March 2017 to June 2022 were selected from Affiliated Hospital of Jiangnan University and Wujin Hospital Affiliated with Jiangsu University.Patient demographics, laboratory tests, intraoperative variables, pathological characteristics were assessed. We also assessed the Child Pugh score and the DSS-B score. Results: Patients were divided into training and testing cohort according to their hospital. Patients in training cohort were divided into high and low difficult groups based on operation time, blood loss and conversion. Higher percentage of patients with malignant liver tumor (87.0% vs. 58.1%; P = 0.003) or history of hepatobiliary surgery (24.1% vs. 7.0%; P = 0.043) in high difficult group than in low difficult group. To improve the difficulty scoring system, we incorporated the history of hepatobiliary surgery and nature of the tumor. A novel difficulty scoring system was established. The results showed that the operation time (P < 0.001), blood loss (P < 0.001), ALT (P < 0.001) and AST (P = 0.001) were associated with the novel difficulty score significantly. Compared with DSS-B, the NDSS has a higher area under the receiver operating characteristic (AUROC) (0.838 vs. 0.814). The nomogram was established according to the NDSS. The AUROCs of the nomogram in training and testing cohort were 0.833 and 0.767. The calibration curves for the probability of adverse event showed optimal agreement between the probability as predicted by the nomogram and the actual probability. Conclusions: We developed a nomogram with the NDSS that can predict the difficulty of LLR. This system could more accurately reflect the difficulty of surgery and help liver surgeons to make the surgical plan and ensure the safety of the operation.

Gluconokinase IDNK Promotes Cell Proliferation and Inhibits Apoptosis in Hepatocellular Carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) is one of the deadliest cancers globally with a poor prognosis. Breakthroughs in the treatment of HCC are urgently needed. This study explored the role of IDNK in the development and progression of HCC. METHODS: IDNK expression was suppressed using short hairpin (shRNA) in BEL-7404 and Huh-7 cells. The expression of IDNK in HCC cells after IDNK knockdown was evaluated by real-time quantitative RT-PCR analysis and Western blot. After IDNK silencing, the proliferation and apoptosis of HCC cells were evaluated by Celigo cell counting, flow cytometry analysis, MTT assay, and caspase3/7 assay. Gene expressions in BEL-7404 cells transfected with IDNK shRNA lentivirus plasmid and blank control plasmid were evaluated by microarray analysis. The differentially expressed genes induced by deregulation of IDNKwere identified, followed by pathway analysis. RESULTS: The expression of IDNK at the mRNA and protein levels was considerably reduced in shRNA IDNK transfected cells. Knockdown of IDNK significantly inhibited HCC cell proliferation and increased cell apoptosis. A total of 1196 genes (585 upregulated and 611 downregulated) were differentially expressed in IDNK knockdown BEL-7404 cells. The pathway of tRNA charging with Z-score = -3 was significantly inhibited in BEL-7404 cells with IDNK knockdown. CONCLUSION: IDNK plays a key role in the proliferation and apoptosis of HCC cells. IDNK may be a candidate therapeutic target for HCC.

Over-expression of ASIC1a promotes proliferation via activation of the ß-catenin/LEF-TCF axis and is associated with disease outcome in liver cancer.

Acid-sensing ion channels 1a (ASIC1a) has been reported to promote migration and invasion in liver cancer. However, the clinical significance and molecular mechanism of ASIC1a in liver cancer remain unknown. In the study, we found that ASIC1a is frequently up-regulated in liver cancer tissues. The over-expression of ASIC1a is associated with advanced clinical stage and poor prognosis. The pro-proliferative of ASIC1a is pH dependent. Knockout of ASIC1a by CRISPR/CAS9 inhibited liver cancer cell proliferation and tumorigenicity in vitro and in vivo through ß-catenin degradation and LEF-TCF inactivation. Our results indicated a potential diagnostic marker and chemotherapeutic target for liver cancer.