TRIM11 suppresses ferritinophagy and gemcitabine sensitivity through UBE2N/TAX1BP1 signaling in pancreatic ductal adenocarcinoma.

Gemcitabine is first-line chemotherapy for pancreatic cancer, however, the development of resistance limits its effectiveness. The tripartite motif-containing 11 (TRIM11) protein plays crucial roles in tumor development and undergoes auto-polyubiquitination to promote interactions in selective autophagy. Therefore, Understanding whether TRIM11 is involved in ferritinophagy and gemcitabine resistance in pancreatic cancer is critical in developing pancreatic cancer therapeutics. TRIM11 expression was validated by Western blot analysis, real-time polymease chain reaction, and immunohistochemical staining. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Colony formation assays were performed to investigate pancreatic ductal adenocarcinomas (PDAC) cell viability. Mouse xenograft model of PDAC cells was established to verify the role of TRIM11 in vivo. Coimmunoprecipitation was used to identify the reciprocal regulation between TRIM11 and UBE2N. In this study, we found that TRIM11 expression were higher in PDAC cells and tissues. TRIM11 overexpression promotes PDAC cell proliferation in vitro and tumor growth in vivo. Decreased expression of TRIM11 in PDAC patients is associated with decreased UBE2N and increased TAX1BP1 expression. Coimmunoprecipitation established that TRIM11 interacts and colocalizes with UBE2N. Mechanistically, TRIM11 promoted gemcitabine resistance and suppressed ferritinophagy through UBE2N-TAX1BP1 signaling. Our findings identify TRIM11 as a key regulator of TAX1BP1 signaling with a crucial role in ferritinophagy and gemcitabine resistance in PDAC.

PTBP3 promotes malignancy and hypoxia-induced chemoresistance in pancreatic cancer cells by ATG12 up-regulation.

Pancreatic ductal adenocarcinoma (PDAC) tumours exhibit a high level of heterogeneity which is associated with hypoxia and strong resistance to chemotherapy. The RNA splicing protein polypyrimidine tract-binding protein 3 (PTBP3) regulates hypoxic gene expression by selectively binding to hypoxia-regulated transcripts. We have investigated the role of PTBP3 in tumour development and chemotherapeutic resistance in human PDAC tissues and pancreatic cancer cells. In addition, we determined the sensitivity of cancer cells to gemcitabine with differential levels of PTBP3 and whether autophagy and hypoxia affect gemcitabine resistance in vitro. PTBP3 expression was higher in human pancreatic cancer than in paired adjacent tissues. PTBP3 overexpression promoted PDAC proliferation in vitro and tumour growth in vivo, whereas PTBP3 depletion had opposing effects. Hypoxia significantly increased the expression of PTBP3 in pancreatic cancer cells in vitro. Under hypoxic conditions, cells were more resistance to gemcitabine. Knockdown of PTBP3 results in decreased resistance to gemcitabine, which was attributed to attenuated autophagy. We propose that PTBP3 binds to multiple sites in the 3'-UTR of ATG12 resulting in overexpression. PTBP3 increases cancer cell proliferation and autophagic flux in response to hypoxic stress, which contributes to gemcitabine resistance.

Comparison of 125 Iodine Seed-Loaded Stents with Different Diameters in Esophageal Cancer: A Multicenter Retrospective Cohort Study.

Currently, there are no recommendations or guidelines concerning the preferred diameter of esophageal stents for palliative treatment, owing to the lack of adequate evidence. We therefore conducted a retrospective cohort study to evaluate whether 18 mm stents would achieve a similar function of dysphagia relief with fewer complications and longer survival compared to 20 mm stents. Esophageal cancer patients who underwent 125 iodine seed-loaded stent placement with a diameter of either 18 mm (n = 103) or 20 mm (n = 54) were included at five hospitals in China. The stabilized inverse probability of treatment weighting (IPTW) was used to control potential confounding factors and bias that are inherent in a retrospective study. The primary endpoint was dysphagia relief. Stent-related complications and overall survival were assessed as the secondary endpoints. In the IPTW-adjusted analysis, no significant difference was found in the dysphagia score between the two groups either at 1 week after stent placement or at the last week before death. Despite a comparable rate of overall complications, there was a significantly lower incidence of severe retrosternal pain (15.4% vs. 32.7%, p = 0.013) and a trend toward longer survival (median survival, 176 days [95% confidence interval (CI) 144 to 209] vs. 109 days [92 to 126], p = 0.057) in the 18 mm group. An irradiated stent with a diameter of 18 mm showed a similar outcome of dysphagia relief to that achieved with a 20 mm diameter stent, but halved the incidence of retrosternal pain after stent placement.

MiR-124 induces autophagy-related cell death in cholangiocarcinoma cells through direct targeting of the EZH2-STAT3 signaling axis.

Cholangiocarcinoma (CCA) is a lethal cancer associated with chronic inflammation that has increased in prevalence in recent decades. The dysregulated expression of microRNAs (miRNAs) has been detected in various types of malignancies, and depending on the target genes this can result in miRNAs functioning as tumor suppressors or oncogenes. In this study, we investigated the role of miR-124 in cholangiocarcinoma (CCA) and found that its expression was significantly downregulated in the tumor tissue of patients and in CCA cell lines. Our results provided evidence that miR-124 induces apoptotic cell death and triggers the autophagic flux in CCA cells. EZH2 and STAT3 were identified as direct targets of miR-124. The effect of miR-124 on EZH2 expression in CCA cells was evaluated using cell transfection, xenotransplantation into nude mice and a luciferase reporter assay. Silencing of EZH2 restored the effects of miR-124, whereas overexpression of EZH2 abrogated the effects of miR-124. Silencing of Beclin1 or ATG5 abrogated the effects of miR-124 or siEZH2. In vivo, overexpression of miR-124 dramatically induced autophagy-related cell death and suppressed tumorigenicity. Taken together, our findings indicated that downregulation of miR-124 expression was associated with disease progression in human CCA and we revealed that miR-124 exerts a tumor suppressive function in CCA by inducing autophagy-related cell death via direct targeting of the EZH2-STAT3 signaling axis.

Irradiation stents vs. conventional metal stents for unresectable malignant biliary obstruction: A multicenter trial.

BACKGROUND & AIMS: Placement of an irradiation stent has been demonstrated to offer longer patency and survival than an uncovered self-expandable metallic stent (SEMS) in patients with unresectable malignant biliary obstruction (MBO). We aim to further assess the efficacy of an irradiation stent compared to an uncovered SEMS in those patients. METHODS: We performed a randomized, open-label trial of participants with unresectable MBO at 20 centers in China. A total of 328 participants were allocated in parallel to the irradiation stent group (ISG) or the uncovered SEMS group (USG). Endpoints included stent patency (primary), technical success, relief of jaundice, overall survival, and complications. RESULTS: The first quartile stent patency time (when 25% of the patients experienced stent restenosis) was 212 days for the ISG and 104 days for the USG. Irradiation stents were significantly associated with a decrease in the rate of stent restenosis (9% vs. 15% at 90 days; 16% vs. 27% at 180 days; 21% vs. 33% at 360 days; p = 0.010). Patients in the ISG obtained longer survival time (median 202 days vs. 140 days; p = 0.020). No significant results were observed in technical success rate (93% vs. 95%; p = 0.499), relief of jaundice (85% vs. 80%; p = 0.308), and the incidence of grade 3 and 4 complications (8.5% vs. 7.9%; p = 0.841). CONCLUSIONS: Insertion of irradiation stents instead of uncovered SEMS could improve patency and overall survival in patients with unresectable MBO. LAY SUMMARY: For patients with unresectable malignant biliary obstruction (MBO), placement of a self-expandable metallic stent (SEMS) is a recommended palliative modality to relieve pruritus, cholangitis, pain, and jaundice. However, restenosis is a main pitfall after stent placement. Data from this first multicenter randomized controlled trial showed that insertion of an irradiation stent provided longer patency and better survival than a conventional metal stent. ClinicalTrials.gov ID: NCT02001779.

Overexpression of Phosphoserine Aminotransferase 1 (PSAT1) Predicts Poor Prognosis and Associates with Tumor Progression in Human Esophageal Squamous Cell Carcinoma.

BACKGROUND/AIMS: Phosphoserine aminotransferase 1 (PSAT1) is over-expressed in many carcinoma tissues, however little is known regarding its expression and function in esophageal carcinogenesis. This study investigated the expression of PSAT1 in human esophageal squamous cell carcinoma (ESCC) tissues to determine the relationship between PSAT1 expression and clinicopathological factors. METHODS: The expression of PSAT1 in 64 surgical resections from esophageal carcinogenesis patients was examined by quantitative RT-PCR and immunohistochemistry and the results were compared with clinicopathological factors. In vitro experiments were performed in ESCC cells overexpressing PSAT1 to measure cell viability and invasion. Tumor formation in vivowas examined by injection of tumor cells into immunocompromised mice subcutaneously. RESULTS: PSAT1 expression was elevated in ESCC tissues compared to normal esophageal tissues. Increased PSAT1 expression was significantly associated with stage of disease, lymph node metastasis, distant metastasis and poor prognosis. In vitro, PSAT1 overexpression promoted ESCC cell proliferation and matrigel invasion. In vivo, injection of mice with ECSS cells overexpressing PSAT1 enhanced tumor formation. Western blot analysis revealed that PSAT1 upregulated the expression and/or activity of GSK3ß/Snail. CONCLUSION: PSAT1 plays a crucial role in the development of ESCC and predicts poor survival. Therefore, PSAT1 may be a promising novel anticancer therapeutic target.

Tumor-associated macrophage-derived CCL20 enhances the growth and metastasis of pancreatic cancer.

Pancreatic cancer is an aggressive malignancy with a high metastatic potential that results in a high mortality rate worldwide. Although macrophages have the potential to kill tumor cells and elicit immune responses against tumors, there is evidence that tumor-associated macrophages (TAMs) promote tumor progression and suppress T-cell responses. CC-chemokine ligand 20 (CCL20) and its unique receptor CC-chemokine receptor 6 (CCR6) are exploited by cancer cells for migration and metastasis and play important roles in the development and progression of cancer. Recent studies have shown that the expression of CCL20 is upregulated in pancreatic cancer; however, the mechanism of action of CCL20 remains to be fully elucidated. In this study, the aberrant expression of CCL20 in TAMs of pancreatic cancer tissue, including metastatic pancreatic cancer tissue, was detected. CCL20 expression was considerably higher in macrophages than in pancreatic cancer cell lines, particularly in interleukin-4-treated (M2) macrophages. Using Boyden chamber assays of pancreatic cancer cells, we found that CCL20 secreted by M2 macrophages promoted the migration, epithelial-mesenchymal transition, and invasion of pancreatic cancer cells. RNA interference results showed that CCR6 is a receptor for CCL20 in pancreatic cancer cells, mediating the increased invasive properties of these cells promoted by CCL20. Using a mouse model, we confirmed the roles of CCR6/CCL20 in promoting pancreatic cancer growth and liver metastasis in vivo Our findings provide insight into the important role of macrophage-secreted CCL20 in pancreatic cancer and implicate CCR6/CCL20 as potential therapeutic targets.

MicroRNA-29a Promotes Pancreatic Cancer Growth by Inhibiting Tristetraprolin.

BACKGROUND/AIMS: The microRNA (miR) 29 family has been studied extensively for its involvement in several diseases, and aberrant expression of its members is associated with tumorigenesis and cancer progression. Here, we examined the role of miR-29a in pancreatic cancer and the involvement of tristetraprolin (TTP). METHODS: We monitored miR-29a and TTP expression in pancreatic cancer by qRT-PCR and western blotting. The effect of miR-29a on pancreatic cancer was determined through MTT assay and migration assay. The results were validated in the tumorigenesis model. RESULTS: We found that miR-29a was up regulated in pancreatic tumor tissues and cell lines and positively correlated with metastasis. Ectopic expression of miR-29a increased the expression of pro-inflammatory factors and epithelial-mesenchymal transition (EMT) markers, through down regulating TTP. TTP was down regulated in tumor tissues, and its ectopic expression decreased cell viability and migration in vitro, inhibited tumor growth and the EMT phenotype in vivo, and reversed the effect of miR-29a on tumor cell proliferation and invasion in vitro and in vivo. CONCLUSION: Our results suggest that miR-29a acts as an oncogene by down regulating TTP and provide the basis for further studies exploring the potential of miR-29a and TTP as biomarkers and targets for the treatment of pancreatic cancer.

MicroRNA-340 Inhibits Esophageal Cancer Cell Growth and Invasion by Targeting Phosphoserine Aminotransferase 1.

BACKGROUND/AIMS: Emerging evidence indicates that microRNA (miR)-340 is downregulated in various human cancers, suggesting that it acts as a tumor suppressor. The aim of the present study was to evaluate the expression and role of miR-340 in human esophageal squamous cell carcinoma (ESCC). METHODS: The expression of miR-340 was examined in 64 paired ESCC and adjacent non-tumor tissues by quantitative real time PCR. The effects of miR-340 on ESCC cell proliferation and metastasis were examined by MTT and Matrigel invasion assays. Tumor growth was assessed by subcutaneous inoculation of cells into BALB/c nude mice. Targets of miR-340 were identified by bioinformatics and verified by luciferase reporter assays, quantitative real-time PCR, and western blotting. RESULTS: MiR-340 was significantly downregulated in ESCC tumor tissues compared to adjacent non-tumor tissues and in ESCC cell lines compared to esophageal endothelial cells. Overexpression of miR-340 inhibited ESCC cell growth, colony formation, and invasion, and tumor growth in a xenograft mouse model. PSAT1 was identified as a direct target of miR-340 and its ectopic expression partially reversed the miR-340 mediated inhibition of viability, invasion and EMT in ESCC cells. The expression of miR-340 was negatively correlated with that of PSAT1 in human ESCC samples. CONCLUSION: MiR-340 functions as a tumor suppressor by modulating the expression of PSAT1 and may contribute to the progression and invasiveness of ESCC.

Application of chemokine receptor antagonist with stents reduces local inflammation and suppresses cancer growth.

Severe pain and obstructive jaundice resulting from invasive cholangiocarcinoma or pancreatic carcinoma can be alleviated by implantation of biliary and duodenal stents. However, stents may cause local inflammation to have an adverse effect on the patients' condition and survival. So far, no efficient approaches have been applied to prevent the occurrence of stents-related inflammation. Here, we reported significantly higher levels of serum stromal cell-derived factor 1 (SDF-1) in the patients that developed stents-associated inflammation. A higher number of inflammatory cells have been detected in the cancer close to stent in the patients with high serum SDF-1. Since chemokine plays a pivotal role in the development of inflammation, we implanted an Alzet osmotic pump with the stents to gradually release AMD3100, a specific inhibitor binding of SDF-1 and its receptor C-X-C chemokine receptor 4 (CXCR4), at the site of stents in mice that had developed pancreatic cancer. We found that AMD3100 significantly reduced local inflammation and significantly inhibited cancer cell growth, resulting in improved survival of the mice that bore cancer. Moreover, the suppression of cancer growth may be conducted through modulation of CyclinD1, p21, and p27 in the cancer cells. Together, these data suggest that inhibition of chemokine signaling at the site of stents may substantially improve survival through suppression of stent-related inflammation and tumor growth.

Nitinol stents loaded with a high dose of antitumor 5-fluorouracil or paclitaxel: esophageal tissue responses in a porcine model.

BACKGROUND: A poor prognosis associated with esophageal cancer leads to surgical resection not suitable for most patients. Nitinol stents loaded with 50% 5-fluorouracil (5-FU) or paclitaxel (PTX), functioning both as a stent and local chemotherapy, could provide a new therapy modality for these patients. OBJECTIVE: To investigate esophageal tissue responses to nitinol stents loaded with 50% 5-FU or PTX implanted in the esophagus of healthy pigs. DESIGN: Twenty-three healthy Bama mini-pigs were randomly divided into 4 groups for stent implantation: group A (PTX stent, n = 13), group B (5-FU stent, n = 8), group C (blank film-covered stent, n = 1), and group D (bare stent, n = 1). Tissue responses were observed by endoscopy or pathologic analyses, and 5-FU or PTX concentrations were measured in the esophagus at the stent implantation site at different time points. SETTING: Animal laboratory. INTERVENTIONS: Endoscopic placement of esophagus stent. MAIN OUTCOME MEASUREMENTS: Endoscopic examination, histology, and drug concentration analysis. RESULTS: In general, the esophageal tissue responses varied according to different parts of 5-FU or PTX stent (middle part [drug-containing part] and bare ends [drug-free part]). Severe tissue responses at the bare ends of the stent included inflammation, ulceration, and granulation. However, the tissue responses were greatly reduced in the middle part of the stent. The drug concentrations in the esophagus that had contact with the 5-FU stent or PTX stent were very high, especially for the first period after implantation, which did not cause obvious tissue damage. LIMITATION: Some subjects had incomplete follow-up because of unexpected deaths and stent migration. CONCLUSION: The nitinol stents loaded with 50% 5-FU or PTX did not cause severe esophageal tissue responses, although there was a large concentration of the drug in these tissues.

Conventional stents versus stents loaded with (125)iodine seeds for the treatment of unresectable oesophageal cancer: a multicentre, randomised phase 3 trial.

BACKGROUND: The combination of stent insertion and single high-dose brachytherapy is a feasible and safe palliative treatment regimen in patients with unresectable oesophageal cancer. We aimed to further assess the efficacy of this treatment strategy compared to a conventional covered stent in patients with dysphagia caused by unresectable oesophageal cancer. METHODS: In this multicentre, single-blind, randomised, phase 3 trial, we enrolled patients with unresectable oesophageal cancer from 16 hospitals in China. We included adult patients (aged ≥ 20 years) with progressive dysphagia, unresectable tumours due to extensive lesions, metastases, or poor medical condition, and with clear consciousness, cooperation, and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-3. Eligible patients were randomly assigned (in 1:1 ratio, no stratification) to receive either a stent loaded with (125)iodine radioactive seeds (irradiation group) or a conventional oesophageal stent (control group). The primary endpoint was overall survival. Survival analyses were done in a modified intention-to-treat group. This study is registered with ClinicalTrials.gov, number NCT01054274. FINDINGS: Between Nov 1, 2009, and Oct 31, 2012, 160 patients were randomly assigned to receive treatment with either an irradiation stent (n=80) or a conventional stent (n=80). During a median follow-up of 138 days (IQR 72-207), 148 stents (73 in the irradiation group and 75 in the control group) were successfully placed into the diseased oesophagus in 148 participants. Median overall survival was 177 days (95% CI 153-201) in the irradiation group versus 147 days (124-170) in the control group (p=0.0046). Major complications and side-effects of the treatment were severe chest pain (17 [23%] of 73 patients in the irradiation group vs 15 [20%] of 75 patents in the control group), fistula formation (six [8%] vs five [7%]), aspiration pneumonia (11 [15%] vs 14 [19%]), haemorrhage (five [7%] vs five [7%]), and recurrent dysphagia (21 [28%] vs 20 [27%]). INTERPRETATION: In patients with unresectable oesophageal cancer, the insertion of an oesophageal stent loaded with (125)iodine seeds prolonged survival when compared with the insertion of a conventional covered self-expandable metallic stent.

Esophageal cancer stem cells express PLGF to increase cancer invasion through MMP9 activation.

Cancer stem cells (CSCs) are a distinct population in tumors and cause cancer relapse and metastasis. Thus, treating CSCs are believed to be potential to cure rapidly growing and highly metastatic cancers. To date, CSCs in esophageal cancer have not been characterized. In the current study, we detected significant higher levels of placental growth factor (PLGF) and matrix metalloproteinase 9 (MMP9) in the esophageal cancers with metastasis, compared to those without metastasis, in which the expression levels of PLGF and MMP9 strongly correlated with each other. Thus, we used a human esophageal cancer cell line, TE-1, to examine the cross talk of PLGF and MMP9. We found that the levels of PLGF in TE-1 cells positively affected the levels of MMP9, while the levels of MMP9 did not affected the levels of PLGF, suggesting that PLGF may activate MMP9 in esophageal cancer cells. Then, we separated PLGF-positive and PLGF-negative TE-1 cells that had been transfected with a GFP reporter under a PLGF promoter by flow cytometry. We found that PLGF-positive cells grew significantly faster than PLGF-negative cells both in vitro and in vivo in a stereotactical implantation model, suggesting that PLGF-positive cells are likely CSCs in esophageal cancer. Taken together, we demonstrate that PLGF-positive cells appear to be CSCs in esophageal cancer, and they may release PLGF to promote cancer metastasis through MMP9 activation.

Placement of a duodenal stents bridge the duodenal papilla may predispose to acute pancreatitis.

BACKGROUND/AIMS: To retrospective evaluate the incidence, predictive factors, and management of acute pancreatitis after placement of duodenal stent in patients with malignant gastroduodenal obstruction. METHODOLOGY: Among 242 patients with symptomatic malignant gastroduodenal obstruction successfully treated with duodenal stent placement, acute pancreatitis occurred in 10 (4.1%) of the patients 1-7 days after stent placement. The variables were analyzed. Univariate and multivariate analysis was performed to evaluate factors predictive of acute pancreatitis. Management of acute pancreatitis also was evaluated. RESULTS: All patients with acute pancreatitis were presented with abdominal pain and distention with vomiting 1-7 days after stent placement, in which 7 patients developed acute janudice. Four patients were cured by fasting and intravenous nutrition, and the remaining 6 cases were managed with percutaneous cholangiography and drain placement (PTCD). Univariate analysis showed acute pancreatitis was associated with location in the descending duodenum (p = 0.001) and stent bridge the duodenal papilla (p < 0.001). Multivariate analysis exhibited that the presence of stent bridged the duodenal papilla (odds ratio (OR), 18.48; 95% CI, 2.298-148.48; p = 0.006) was independent predictors of acute pancreatitis. CONCLUSIONS: Acute pancreatitis is an uncommon early complication of placement of duodenal stents in patients with malignant gastroduodenal obstruction. Acute pancreatitis occurred most commonly in descending duodenum, and in patients with stent bridged the duodenal papilla. Stent bridged the duodenal papilla may be the most important predictors for acute pancreatitis. Acute pancreatitis can be managed conservatively or by PTCD when developed to acute jaundice.

[The study of clinical value of transarterial chemical perfusion as second-line therapy for late stage pancreatic cancer].

OBJECTIVE: To discuss arterial infusion chemotherapy as second-line treatment for advanced pancreatic carcinoma salvage after failed vein chemotherapy. METHODS: 35 cases with IV stage pancreatic carcinoma, all cases are failed first-line chemotherapy of Gemcitabine. Via femoral artery puncture, gastroduodenal artery, the dorsal pancreatic artery, pancreatic artery, pancreatic tail artery, the rib waist artery, superior mesenteric artery and tumor related to blood supply artery intubation and chemical drug perfusion. Plan: Cisplatin 30 mg/m², Gemcitabine 1 000 mg/m². Treatment for every 3-4 weeks, there is no limit on the total number. RESULTS: 35 cases were local chemotherapy for 217 cycles, at least 1 cycle, a maximum of 9 cycles, 6.2 cycles on average. Among which: CR 1 case, PR 6 cases, SD 15 cases, effective rate (CR+PR) is 20%, disease control rate (DCR) is 68.75%. The median survival time was 9.6 months. The median TTP was 3.7 months. Total effective rate of CBR , the stability rate of CBR and inefficiency rate of CBR were 51.4%, 25.7% and 22.9% respectively. Pain score improvement 88.57% (31/35), 42.86% (15/35) Pain relief last for 3-20 days ( median time 11 days). 17.14% (6/35) Pain relief last for more than 20 days. Pain relief maintain the most elderly 160 days. Half of the patients have different degree of side reaction, III, IV degree leukopenia accounted for 17.14% (6/35), 8.57% (3/35). CONCLUSION: The arterial perfusion chemotherapy as second-line treatment of advanced pancreatic cancer salvage is of clinical value, with better disease control rate and the rate of pain relief.

HP1BP3 promotes tumor growth and metastasis by upregulating miR-23a to target TRAF5 in esophageal squamous cell carcinoma.

HP1BP3, an ubiquitously expressed nuclear protein belonging to the H1 histone family of proteins, plays an important role in cell growth and viability. Recently, it was reported that HP1BP3 exclusively regulates miRNA biogenesis by enhancing transcriptional miRNA processing. Although HP1BP3 has previously been implicated in common cancer types, the mechanistic functions and effects of HP1BP3 and its role in the prognosis of esophageal squamous cell carcinoma (ESCC) remain unclear. Here, we report that ESCC tissues and cell lines show increased endogenous expression of HP1BP3. Knockdown of HP1BP3 in TE-1 cells significantly inhibited tumor growth and metastasis in vivo emphasizing its role in cell proliferation and invasion. In contrast, overexpression of HP1BP3 significantly enhanced tumor growth and metastasis in Eca-109 cells. Further, we found that HP1BP3 regulates these functions by upregulating miR-23a, which directly binds to the 3'UTR region of TRAF5 downstream to alter cell survival and proliferation. Our findings describe a role for HP1BP3 in promoting tumor growth and metastasis by upregulating miR-23a to target TRAF5 in esophageal cancer. This study provides novel insights into the potential of targeting miRNAs for therapy and as clinical markers for cancer progression.

Treatment of aerodigestive fistulas with a novel covered metallic Y-shaped segmented airway stent customized with the assistance of 3D printing.

BACKGROUND: The management of aerodigestive fistula remains challenging. An airway stent that matches well with the individual geometry of the airway is needed for the treatment of the aerodigestive fistula. This study aimed to evaluate the feasibility of a novel covered metallic segmented Y-shaped airway stent customized with the assistance of 3D printing in aerodigestive fistulas involving the carina and distal bronchi and to compare the flexibility of the novel stent with the conventional wholly knitted stent. METHODS: In the flexibility study, we measured the longitudinal bending force and spring-back force of the segmented stent and wholly knitted stent. Patient-specific stents that were individually customized with the assistance of 3D printing technology were implanted in 26 patients with aerodigestive fistulas. The technical success, clinical success, Karnofsky performance status (KPS), and stent-related complications were recorded. RESULTS: The bending force and spring-back force of the segmented stent were significantly lower than those of the wholly knitted stent. Stent deployment was technically successful in all patients. Clinical success was obtained in 21 patients. The KPS of patients after the stenting procedure improved significantly compared with that before stenting (P<0.001). During follow-up, granulation tissue proliferation, sputum retention, stent migration, and intolerance of the stent were found in 2, 5, 1, and 1 patient, respectively. CONCLUSIONS: The segmented metallic Y-shaped airway stent had greater flexibility than the wholly knitted stent in an ex vivo setting. Implantation of the segmented stent individually customized with the aid of 3D printing is feasible in treating aerodigestive fistulas involving the carina and bronchi distal to the carina.

Customization of stent design for treating malignant airway stenosis with the aid of three-dimensional printing.

BACKGROUND: The treatment of malignant stenosis involving the carina or bronchi is challenging due to complicated anatomy with individual variation, which makes it necessary to customize stents for each patient. Therefore, this study aims to evaluate the feasibility of a novel metallic segmented airway stent customized with the aid of three-dimensional (3D) printing for such cases. METHODS: The stents were individually customized with the aid of a 3D printed mold based on computed tomography (CT) images according to the anatomical features of the airway. A segmented design was applied on the junction part of the main stem and the branches to fit the dynamic changes of the carina angle. In 12 patients with airway stenosis caused by malignancies including esophageal cancer (EC) and lung cancer (LC), the stents were implanted. The technical and clinical success of the stenting procedure, Hugh-Jones (HJ) classification, Karnofsky performance status (KPS), and stent-related complications of patients were evaluated. RESULTS: The stenting procedure was technically successful in all patients, and 11 patients showed significant palliation of dyspnea after stenting. The HJ and KPS classification of patients after stent insertion improved significantly compared with those before stenting (P=0.003 and P=0.006, respectively). During follow-up, granulation tissue proliferation and sputum retention were found in two and four patients, respectively. CONCLUSIONS: This study shows that the implantation of a novel stent designed with the aid of 3D printing is feasible for relieving dyspnea and improving performance status of patients with inoperable malignant stenosis involving the carina or bronchi.

Preliminary Experience With a Novel Metallic Segmented Transcordal Stent Modified With Three-Dimensional Printing for Inoperable Malignant Laryngotracheal Stenosis.

BACKGROUND: This study aims to assess the feasibility of a novel metallic segmented transcordal stent modified with three-dimensional (3D) printing for treating inoperable malignant laryngotracheal stenosis and the tolerability of the stent. METHODS: This was a retrospective study. The stents were individually customized with the aid of 3D printing model based on the anatomic features of each patient's airway. The stent was composed of two separate segments that corresponded to the larynx and the upper trachea. The stents were barrel-shaped at the proximal end to prevent migration. The proximal end of the stent was located slightly above the vocal cord. The technical and clinical success of stenting procedure, patient tolerability, and stent-related complications of patients were evaluated. RESULTS: Ten patients with dyspnea caused by malignant laryngotracheal stenosis underwent implantation of such stents. Technical and clinical success of the stenting procedure were achieved in all patients. For all patients, basic communication in life could be maintained by speaking softly. During follow-up, one patient showed intolerance to the stent, and the stent was retrieved 2 weeks after stenting. Stent migration was found in one patient, and the position of the stent was readjusted. Granulation tissue proliferation was found in two patients and was treated with cryotherapy by bronchoscopy. There were no deaths associated with stenting. CONCLUSIONS: The individually customized metallic segmented transcordal stent is feasible and tolerable for patients with inoperable malignant laryngotracheal stenosis. The implantation of this stent may serve as a novel alternative treatment for patients who are not suitable for surgery or tracheotomy.

Identification of Critical Genes and Proteins for Stent Restenosis Induced by Esophageal Benign Hyperplasia in Esophageal Cancer.

This study was conducted to explore the potential genes and proteins associated with esophagus benign hyperplasia induced by esophageal stents. Five patients with esophageal cancer subjected to esophageal stent placement were enrolled in this study. Long non-coding RNA (lncRNA) sequencing and tandem mass tag quantitative proteomics analysis were performed by using the collected hyperplastic samples and adjacent non-hyperplastic tissues. Differentially expressed (DE) RNAs and proteins were analyzed, followed by functional enrichment analysis, protein-protein interaction (PPI) network analysis, and competitive endogenous RNA (ceRNA) network construction. Venn analysis was performed to extract the overlaps between DE mRNAs and DE proteins and the expression correlations between DE mRNA and proteins were analyzed. Results showed that total 642 DE RNAs (457 mRNA and 185 lncRNAs) and 256 DE proteins were detected. DE mRNAs (such as MAOB, SDR16C5, and FOSL1) were enriched in oxidation-reduction process-associated functions. PPI network was comprised of 175 nodes and 425 edges. VEGFA was a significant node with the highest degree. LncRNA-mRNA network with three subnetworks (C1, C2, C3) was constructed for lncRNAs with more than 15 gene targets. RP11-58O9.2 was a significant lncRNA with the most target genes and RP11-667F14.1 regulated more than 20 targets. FOSL1 was a common target of the two lncRNAs. Function analysis showed that DE lncRNAs were involved in the HTLV-I infection (RP11-58O9.2 and RP11-667F14.1) and IL-17 signaling pathways (RP11-5O24.1 and RP11-58O9.2). Total 11 DE mRNAs were overlapped with DE proteins, among which MAOB and SDR16C5 showed positive correlations between mRNA and protein expression. Function analysis showed that MAOB was enriched in oxidation-reduction process and its protein was closely related with response to lipopolysaccharide. VEGFA, FOSL1, MAOB, SDR16C5, RP11-58O9.2, RP11-667F14.1, and RP11-288A5.2 may be served as genetic targets for preventing stent restenosis in esophageal cancer.