MicroRNA-224 Promotes Pancreatic Cancer Cell Proliferation and Migration by Targeting the TXNIP-Mediated HIF1α Pathway.

BACKGROUND/AIMS: MicroRNAs (miRNAs) have been shown to participate in the development of pancreatic ductal adenocarcinoma (PDAC) by modulating multiple cellular processes. Increased miR-224 expression enhances proliferation and metastasis in human cancers. This study aimed to investigate the role of miR-224 and its underlying mechanism of action in PDAC. METHODS: BrdU, MTT, and cell migration assays were performed to determine cell proliferation, viability, and migration, respectively. The binding sites of miR-224 were identified using a luciferase reporter system, whereas protein expression of target genes was determined by immunoblotting and immunofluorescence analyses. A BALB/c nude mouse xenograft model was used to evaluate the role of miR-224 in vivo. RESULTS: We demonstrated that miR-224 expression was enhanced in PDAC cells and tissues, and was related to migration and proliferation. Noticeably, miR-224 overexpression promoted the proliferation, migration, and metastasis of Panc1 cells, while miR-224 inhibition had the reverse effect on PDAC cells. Moreover, we found that thioredoxin-interacting protein (TXNIP) is a target of miR-224. The results also indicated that miR-224 inversely regulated TXNIP by binding directly to its 3'-untranslated region, which resulted in the activation of hypoxia-inducible factor 1α (HIF1α). Further, either TXNIP re-expression or HIF1α depletion abolished the effects of miR-224 on the proliferation and migration of PDAC cells in vitro and in vivo. Regarding the relationship of TXNIP and HIF1α, we found that TXNIP mediated the nuclear export of HIF1α and its degradation by forming a complex with HIF1α. CONCLUSION: The miR-224-TXNIP-HIF1α axis may be useful in developing novel therapies for PDAC.

Circadian clock gene expression regulates cancer cell growth through glutaminase.

Glutamine is an essential amino acid for malignant tumor cells. Glutaminase that metabolizes glutamine reaches a maximum expression in tumors immediately before the maximum proliferation rate. Tumor cells grow at different rates during the day. We postulated that the activity of glutaminase in tumor cells is subject to the regulation of circadian clock gene. We measured glutaminase by western blot analysis and circadian clock gene expression by real-time polymerase chain reaction in the liver and tumor cells at six equispaced time points of the day in individual mice of a 12/12 h light/dark schedule. The results showed that the tumor-bearing mice, under normal diurnal conditions, are circadianly entrained, as reflected by the normal host locomotor activity rhythms and rhythmic liver clock gene expression. The tumors within these mice are also circadianly organized, as reflected by circadian clock gene (Bmal1) expression. What is most remarkable is that kidney-type glutaminase also showed circadian rhythms in the same pattern with tumor circadian clock gene expression in liver cancer xenograft model, indicating that conditionally inhibiting glutaminase activity may provide a new target for cancer therapy.

Preliminary efficacy and safety of YSCH-01 in patients with advanced solid tumors: an investigator-initiated trial.

OBJECTIVE: To evaluate the safety and preliminary efficacy of YSCH-01 (Recombinant L-IFN adenovirus) in subjects with advanced solid tumors. METHODS: In this single-center, open-label, investigator-initiated trial of YSCH-01, 14 patients with advanced solid tumors were enrolled. The study consisted of two distinct phases: (1) the dose escalation phase and (2) the dose expansion phase; with three dose groups in the dose escalation phase based on dose levels (5.0×109 viral particles (VP)/subject, 5.0×1010 VP/subject, and 5.0×1011 VP/subject). Subjects were administered YSCH-01 injection via intratumoral injections. The safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0, and the efficacy evaluation was performed using Response Evaluation Criteria in Solid Tumor V.1.1. RESULTS: 14 subjects were enrolled in the study, including 9 subjects in the dose escalation phase and 5 subjects in the dose expansion phase. Of the 13 subjects included in the full analysis set, 4 (30.8%) were men and 9 (69.2%) were women. The most common tumor type was lung cancer (38.5%, 5 subjects), followed by breast cancer (23.1%, 3 subjects) and melanoma (23.1%, 3 subjects). During the dose escalation phase, no subject experienced dose-limiting toxicities. The content of recombinant L-IFN adenovirus genome and recombinant L-IFN protein in blood showed no trend of significant intergroup changes. No significant change was observed in interleukin-6 and interferon-gamma. For 11 subjects evaluated for efficacy, the overall response rate with its 95% CI was 27.3% (6.02% to 60.97%) and the disease control rate with its 95% CI was 81.8% (48.22% to 97.72%). The median progression-free survival was 4.97 months, and the median overall survival was 8.62 months. In addition, a tendency of decrease in the sum of the diameters of target lesions was observed. For 13 subjects evaluated for safety, the overall incidence of adverse events (AEs) was 92.3%, the overall incidence of adverse drug reactions (ADRs) was 84.6%, and the overall incidence of >Grade 3 AEs was 7.7%, while no AEs/ADRs leading to death occurred. The most common AEs were fever (69.2%), nausea (30.8%), vomiting (30.8%), and hypophagia (23.1%). CONCLUSIONS: The study shows that YSCH-01 injections were safe and well tolerated and exhibited preliminary efficacy in patients with advanced solid tumors, supporting further investigation to evaluate its efficacy and safety. TRIAL REGISTRATION NUMBER: NCT05180851.

RP11-462C24.1 suppresses proliferation and invasion of colorectal carcinoma cells by regulating HSP70 through PI3K/AKT signaling pathway.

Colorectal cancer (CRC) is the third leading cause of cancer-related death around the world. In this study, we investigated the roles of LncRNA RP11-462C24.1 in CRC. The expressions of RP11-462C24.1 in CRC tissues and cells were measured. Then, the effects of RP11-462C24.1 on CRC proliferation, cell cycle, apoptosis, and invasion were evaluated both in vivo and in vitro; Last, the underlying mechanisms of concerning the signaling pathway regulated by RP11-462C24.1 was determined. From the results, we found that RP11-462C24.1 was significantly decreased in CRC tumor tissues and the CRC cell lines, which were most significant in SW480 and HT-29 cell lines; moreover, transient overexpression of RP11-462C24.1 suppressed the growth and migration while promoted apoptosis of SW480 and HT-29 cells, while knockdown of RP11-462C24.1 has shown the opposite effects; RP11-462C24.1 may also inhibit the growth of CRC tumors in xenograft mice models; additionally, 70 kD heat shock proteins (HSP70) has been identified as one of the most significantly deferentially expressed genes by RNA-seq, and we further confirmed that RP11-462C24.1 may affect the growth and metathesis of CRC cells via regulating HSP70 and PI3K/AKT signaling pathway. In summary, these results indicated that RP11-462C24 may function as a tumor suppressor in the development of CRC.

The Learning Curve of Transareola Single-site Laparoendoscopic Thyroidectomy: CUSUM Analysis of a Single Surgeon's Experience.

BACKGROUND: Transareola single-site laparoendoscopic thyroidectomy (TASSET) is a rapidly advancing minimally invasive procedure. The purpose of this study was to evaluate the learning curve for TASSET. SUBJECTS AND METHODS: Forty-five consecutive patients were prospectively divided into group 1 (initial phase), group 2 (intermediate phase), and group 3 (advanced phase) according to their surgical order (15 patients in each group). The operative time, operative blood loss, duration of hospital stay, postoperative pain, and postoperative complications were compared using phases. RESULTS: Statistically significant differences were observed in the different learning phases, among operative time (P<0.05), operative blood loss (P<0.05), hospital stay (P<0.05), and postoperative pain (P<0.05). The postoperative complication rate was low (3/45). CONCLUSIONS: Learning curve of the TASSET are improved synchronized at different phases and technical indicators. The establishment of operative space take longer time to skilled master.

Transareola single-site laparoendoscopic bilateral thyroidectomy.

BACKGROUND: Transareola single-site endoscopic thyroidectomy has been successfully established as a surgical approach. This study investigated the feasibility and safety of transareola single-site endoscopic thyroidectomy for bilateral thyroid disease. PATIENTS AND METHODS: Twelve patients who underwent bilateral thyroidectomy were enrolled in this study. The surgical outcomes were analyzed, including operation time, intraoperative bleeding volume, postoperative pain score, and cosmetic satisfaction score. RESULTS: All patients underwent successful transareola single-site endoscopic bilateral thyroidectomy, and no patient was semiconverted to three-port endoscopic surgery or open surgery. Seven patients underwent bilateral partial thyroidectomy, and 5 patients underwent subtotal thyroidectomy plus contralateral partial thyroidectomy. The mean operation time was 165±23.8 minutes (range, 142-185 minutes). The mean intraoperative bleeding volume was 27.3±12.3 mL (range, 20-45 mL). The mean postoperative wound drainage was 121±45.8 mL (range, 85-137 mL). The drainage tube was removed 3-4 days after surgery. The mean visual analog scale score was 3.3±2.5 (range, 1-5) at 24 hours postoperatively. The patients were followed up for 2 month with no complaint of chest wall wound pain and numbness. The mean cosmetic satisfaction score was 9.55±0.8 (range, 8-10). CONCLUSIONS: Transareola single-site endoscopic bilateral thyroidectomy is feasible and safe and has the advantages of high cosmetic satisfaction.

Transareola single-site endoscopic thyroidectomy: clinical study of 28 cases with thyroid nodules.

OBJECTIVES: To investigate the feasibility and safety of transareola single-site endoscopic thyroidectomy. SUBJECTS AND METHODS: Twenty-eight patients with thyroid nodules were involved in this study. An incision was cut on a single areola, and a laparoendoscope apparatus and an operating apparatus were implanted. The thyroid gland was exposed using the neck suture suspension technique, and the damaged thyroid gland was removed with an ultrasonic scalpel. The operation time, intraoperative bleeding volume, postoperative pain score, and cosmetic satisfaction score were calculated. RESULTS: Unilateral subtotal thyroidectomy was performed in 12 cases, unilateral partial thyroidectomy in 14 cases, and bilateral partial thyroidectomy in 2 cases. For the former 14 cases, the operation time was 145-205 minutes, with a mean duration of 170 minutes; the operation time ranged from 125 to 150 minutes, with a mean of 135 minutes, for the latter 14 cases. The intraoperative bleeding volume was 15-40 mL, with a mean of 25 mL. The total postoperative wound drainage was 80-135 mL, with a mean of 110 mL. The drainage tube was removed 3-4 days after surgery. The visual analog scale score was 1-5 at 24 hours postoperatively, with a mean score of 3.10. Postoperative pathological examination diagnosed thyroid adenoma in 11 cases and nodular goiter in 17 cases. CONCLUSIONS: Transareola single-site endoscopic thyroidectomy is feasible and safe and has the advantages of a covert incision, small subcutaneous separation area, and high cosmetic satisfaction. The operation time shortens with the increasing number of patients undergoing operations.

STAT3 repressed USP7 expression is crucial for colon cancer development.

Interleukin-6 (IL-6) induced STAT3 activation is viewed as crucial for multiple tumor growth and metastasis, including colon cancer. However, the molecular mechanisms remain largely unexplored. Here, we show that expression of ubiquitin-specific protease 7 (USP7), a deubiquitylating enzyme, is decreased in STAT3-positive tumors. IL-6 administration or transfection of a constitutively activated STAT3 in SW480 cells also repressed USP mRNA expression. Using luciferase reporter and ChIP assay, we found that STAT3 bound to the promoter region of USP7 and inhibited its activity through recruiting HDAC1. As a result of the decline of USP7 expression, endogenous P53 protein level was decreased. Thus, our results suggest a previously unknown STAT3-USP7-P53 molecular network controlling colon cancer development.