Gradual Transverse Transport of Naturally Tibialized Fibula Using Hexapod Frames to Treat Neglected Type V Tibial Segmental Defects.

OBJECTIVE: Although several reconstructive methods have been developed to manage large segmental tibial bone defects including bone transport (distraction osteogenesis), contralateral fibular graft, allograft, tibiofibular synostosis, Masquelet technique, and 3D printed scaffold, neglected large tibial defects in adults remain challenging problems. This study describes gradual transverse transport of naturally tibialized fibula using hexapod frames in management of adult patients with neglected large tibial defects. METHODS: We retrospectively reviewed four cases of transverse transport of naturally tibialized fibula from November 2018 to February 2022. We measured the length of the tibial defect and the transported fibular segment, the mid-diaphyseal diameter and cortical thickness of the affected fibula, contralateral fibula, and tibia. The parameters measured both preoperatively and postoperatively were leg length discrepancy, hip-knee-ankle angle, medial proximal tibial angle, posterior proximal tibial angle, lateral distal tibial angle, range of motion of the knee and ankle joints, and Lower Extremity Functional Scores (LEFS). Patients' satisfaction rates using Likert scale were also recorded. RESULTS: Among four female patients, three suffered from tibial osteomyelitis, and one was due to congenital pseudarthrosis of the tibia. The average follow-up time was 2.7 ± 1.4 years. The average length of tibial defect was 14.0 ± 0.8 cm. The average preoperative shortening of the affected leg was 9.0 ± 2.5 cm, which changed to 0.6 ± 0.8 cm postoperatively. The median length of the transported fibular segment was 15.2 cm. Two patients had varus deformity, two had recurvatum, and one had procurvatum preoperatively. Postoperative radiological measurement showed all deformities corrected and no ankle valgus deformity developed during follow-up. All patients achieved union and can fully weight bear on the affected extremity. The average fixator time was 12.9 ± 2.9 months. The average preoperative and postoperative LEFS, respectively, were 53.5 ± 5.0, 70.5 ± 1.3, with a significant difference (p = 0.003). Three patients reported very satisfied with the outcome, and one patient reported satisfied. Three patients had pin tract infections, and one patient had skin necrosis which healed after additional surgery. One patient had surgical release of the hamstring tendons due to flexion contracture of the knee. Two patients had 15° of reduction in ankle range of motion. One patient had transient common peroneal nerve palsy which spontaneously recovered within 6 weeks. CONCLUSION: The transverse transport of naturally tibialized fibula was both a safe and effective method to treat the long-standing type V tibial segmental defect.

Optimizing Outcomes in Distal Tibial Deformity Correction: The Role of Supramalleolar Osteotomy with Computer-assisted Hexapod External Fixator.

OBJECTIVE: Distal tibial deformities can significantly impact patients if left uncorrected, often leading to pain, alterations in gait, and the eventual development of post-traumatic arthritis. The criteria for surgical correction in these patients continues to be a subject of debate, while supramalleolar osteotomy (SMO) is an effective method for correcting distal tibial deformities. The purpose of this study was to evaluate and compare the clinical results of SMO using internal fixation or using computer-assisted hexapod external fixator in the treatment of distal tibial deformity. METHODS: A retrospective study was conducted on 290 patients who underwent SMO between June 2015 and January 2023. Forty-four patients met the inclusion and exclusion criteria. Among the participants, 19 underwent SMO combined with a computer-assisted hexapod external fixator, while 25 received SMO with plate and screw internal fixation. The tibial anterior surface (TAS) angle, tibial lateral surface (TLS) angle, the tibiotalar (TT) angle and the talocrural (TC) angle were assessed on weight-bearing X-ray films. Functional assessments were performed according to the American Orthopedic Foot and Ankle Society (AOFAS) ankle-hindfoot score. RESULTS: The study followed patients for an average duration of 31.7 ± 15.3 months, with a range from 12 to 67 months. Successful bone union was achieved in all cases. For patients treated with the computer-assisted hexapod external fixator, significant improvements were observed: the mean deviation in sagittal plane deformity parameters decreased from 14.3 ± 10.4 degrees preoperatively to 2.8 ± 3.8 degrees postoperatively (p < 0.05). Similarly, coronal plane deformity parameters showed a reduction from 25.9 ± 22.5 degrees preoperatively to 5.9 ± 11.0 degrees postoperatively (p < 0.05). The AOFAS ankle-hindfoot score improved markedly from 66.0 ± 14.9 to 86.1 ± 11.7 points (p < 0.05). For patients undergoing internal fixation, the absolute difference in coronal plane parameters improved from 15.4 ± 12.6 degrees preoperatively to 3.7 ± 3.4 degrees postoperatively (p < 0.05). A significant enhancement in AOFAS ankle-hindfoot score was also noted, increasing from 68.3 ± 14.3 points to 79.4 ± 13.5 points (p < 0.05). There were no significant differences in gender, side, follow-up time, postoperative deviation of deformity, pre- or postoperative AOFAS between the two groups. CONCLUSION: In conclusion, comprehensive preoperative planning of SMO combined with either internal fixation or a hexapod external fixator for treating distal tibial deformities can achieve satisfactory outcomes. The utilization of a computer-assisted hexapod external fixator facilitates a gradual and precise correction process, which proved to be an effective and relatively safe method.

Treatment of Fourth Metatarsal Brachymetatarsia Using Distraction Osteogenesis with External Fixator: Surgical Techniques, Outcomes and Complications.

OBJECTIVE: Surgical technique in distraction osteogenesis for the treatment of brachymetatarsia can influence the final prognosis. However, there are currently no standardized guidelines for surgical procedures and complication management. The aim of this study is to investigate the effect of bone lengthening with external fixation by minimally invasive osteotomy based on Ilizarov technique in the treatment of congenital brachymetatarsia. METHODS: A retrospective study was conducted on patients with congenital brachymetatarsia treated by metatarsal lengthening, from June 2017 to December 2020. There were 11 patients with 17 shorted fourth metatarsals, including 10 females and 1 male, with age of 24.6 ± 4.5 years (16-31 years). Six patients were bilaterally involved. Orthofix external fixator mini track was installed through dorsal approach and the fourth MTP joints were temporarily fixed by Kirschner wire. Bone lengthening was performed after a minimally invasive osteotomy at the proximal metatarsals. American Orthopedic Foot and Ankle Society (AOFAS) lesser metatarsophalangeal-interphalangeal (MTP-IP) scores, metatarsal length, complications were recorded. Statistical comparison was performed using the paired t-student test for pre- and postoperative AOFAS MTP-IP scores. RESULTS: Patients were followed up for 55 ± 10.8 months. The mean length of the fourth metatarsal bone was 49.9 ± 2.9 mm preoperatively. The mean metatarsal shortage was 18.8 ± 3.1 mm. The mean lengthening achieved was 19.8 ± 3.3 mm, with a lengthening ratio of 39.7% ± 6.6%. The lengthened callus ossified completely at 3-4 months after operation. All patients were satisfied with the results of lengthening. The AOFAS scores were improved significantly from 83.7 ± 4.2 preoperatively to 93.2 ± 2.7 postoperatively (t = -10.27, p < 0.001). One patient with traumatic metatarsophalangeal joint subluxation was treated by joint reduction and Kirschner wire fixation. One patient had metatarsophalangeal joint release and Kirschner wire fixation due to flexion contracture. Pin tract infections were controlled by wound care and antibiotics in 6 patients. All patients had no nonunion, necrosis of toes, and sensory disturbance of toes. CONCLUSION: Metatarsal lengthening by minimally invasive osteotomy with external fixator had satisfactory results in the treatment of congenital brachymetatarsia.

Tumor-derived apoptotic extracellular vesicle-mediated intercellular communication promotes metastasis and stemness of lung adenocarcinoma.

Apoptosis has long been recognized as a significant mechanism for inhibiting tumor formation, and a plethora of stimuli can induce apoptosis during the progression and treatment of tumors. Moreover, tumor-derived apoptotic extracellular vesicles (apoEVs) are inevitably phagocytosed by live tumor cells, promoting tumor heterogeneity. Understanding the mechanism by which apoEVs regulate tumor cells is imperative for enhancing our knowledge of tumor metastasis and recurrence. Herein, we conducted a series of in vivo and in vitro experiments, and we report that tumor-derived apoEVs promoted lung adenocarcinoma (LUAD) metastasis, self-renewal and chemoresistance. Mechanistically, we demonstrated that apoEVs facilitated tumor metastasis and stemness by initiating the epithelial-mesenchymal transition program and upregulating the transcription of the stem cell factor SOX2. In addition, we found that ALDH1A1, which was transported by apoEVs, activated the NF-κB signaling pathway by increasing aldehyde dehydrogenase enzyme activity in recipient tumor cells. Furthermore, targeting apoEVs-ALDH1A1 significantly abrogated these effects. Collectively, our findings elucidate a novel mechanism of apoEV-dependent intercellular communication between apoptotic tumor cells and live tumor cells that promotes the formation of cancer stem cell-like populations, and these findings reveal that apoEVs-ALDH1A1 may be a potential therapeutic target and biomarker for LUAD metastasis and recurrence.

SUMOylation-triggered ALIX activation modulates extracellular vesicles circTLCD4-RWDD3 to promote lymphatic metastasis of non-small cell lung cancer.

Lymph node (LN) metastasis is one of the predominant metastatic routes of non-small cell lung cancer (NSCLC) and is considered as a leading cause for the unsatisfactory prognosis of patients. Although lymphangiogenesis is well-recognized as a crucial process in mediating LN metastasis, the regulatory mechanism involving lymphangiogenesis and LN metastasis in NSCLC remains unclear. In this study, we employed high-throughput sequencing to identify a novel circular RNA (circRNA), circTLCD4-RWDD3, which was significantly upregulated in extracellular vesicles (EVs) from LN metastatic NSCLC and was positively associated with deteriorated OS and DFS of patients with NSCLC from multicenter clinical cohort. Downregulating the expression of EV-packaged circTLCD4-RWDD3 inhibited lymphangiogenesis and LN metastasis of NSCLC both in vitro and in vivo. Mechanically, circTLCD4-RWDD3 physically interacted with hnRNPA2B1 and mediated the SUMO2 modification at K108 residue of hnRNPA2B1 by upregulating UBC9. Subsequently, circTLCD4-RWDD3-induced SUMOylated hnRNPA2B1 was recognized by the SUMO interaction motif (SIM) of ALIX and activated ALIX to recruit ESCRT-III, thereby facilitating the sorting of circTLCD4-RWDD3 into NSCLC cell-derived EVs. Moreover, EV-packaged circTLCD4-RWDD3 was internalized by lymphatic endothelial cells to activate the transcription of PROX1, resulting in the lymphangiogenesis and LN metastasis of NSCLC. Importantly, blocking EV-mediated transmission of circTLCD4-RWDD3 via mutating SIM in ALIX or K108 residue of hnRNPA2B1 inhibited the lymphangiogenesis and LN metastasis of NSCLC in vivo. Our findings reveal a precise mechanism underlying SUMOylated hnRNPA2B1-induced EV packaging of circTLCD4-RWDD3 in facilitating LN metastasis of NSCLC, suggesting that EV-packaged circTLCD4-RWDD3 could be a potential therapeutic target against LN metastatic NSCLC.

SERPINB5 is a prognostic biomarker and promotes proliferation, metastasis and epithelial-mesenchymal transition (EMT) in lung adenocarcinoma.

BACKGROUND: Serine protease inhibitors clade B serpins (SERPINBs) are the largest subclass of protease inhibitors, once thought of as a tumor suppressor gene family. However, some SERPINBs exhibit functions unrelated to the inhibition of catalytic activity. METHODS: The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Gene Set Cancer Analysis (GSCA), and cBioPortal databases were utilized to investigate SERPINBs expression, prognostic correlation, and genomic variation in 33 cancer types. We also conducted a comprehensive transcriptome analysis in multiple lung adenocarcinoma (LUAD) cohorts to reveal the molecular mechanism of SERPINB5 in LUAD. Then, qPCR and immunohistochemistry were used to verify the expression and prognostic value of SERPINB5 in LUAD patients. Furthermore, knockdown and overexpression of SERPINB5 in LUAD cell lines were performed to evaluate cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). RESULTS: The expression of SERPINB5 was upregulated and demethylated in LUAD, and its abnormally high expression was significantly correlated with poor overall survival (OS). In addition, the expression of SERPINB5 was analyzed to determine its prognostic value in LUAD and confirmed that SERPINB5 was an independent predictor of LUAD in TCGA and GEO cohorts and qPCR validation with 106 clinical samples. At last, A knockdown of SERPINB5 in LUAD cells reduced proliferation, migration, and EMT. Proliferation, migration, and invasion are promoted by the overexpression of SERPINB5. CONCLUSION: Therefore, SERPINB5 has shown potential as a prognostic biomarker for LUAD, and it may become a potential therapeutic target for lung adenocarcinoma.

Intrinsic Immunogenic Tumor Cell Death Subtypes Delineate Prognosis and Responsiveness to Immunotherapy in Lung Adenocarcinoma.

Recent studies have highlighted the combination of activation of host immunogenic cell death (ICD) and tumor-directed cytotoxic strategies. However, overall multiomic analysis of the intrinsic ICD property in lung adenocarcinoma (LUAD) has not been performed. Therefore, the aim of this study was to develop an ICD-based risk scoring system to predict overall survival (OS) and immunotherapeutic efficacy in patients. In our study, both weighted gene co-expression network analysis (WGCNA) and LASSO-Cox analysis were utilized to identify ICDrisk subtypes (ICDrisk). Moreover, we identify genomic alterations and differences in biological processes, analyze the immune microenvironment, and predict the response to immunotherapy in patients with pan-cancer. Importantly, immunogenicity subgroup typing was performed based on the immune score (IS) and microenvironmental tumor neoantigens (meTNAs). Our results demonstrate that ICDrisk subtypes were identified based on 16 genes. Furthermore, high ICDrisk was proved to be a poor prognostic factor in LUAD patients and indicated poor efficacy of immune checkpoint inhibitor (ICI) treatment in patients with pan-cancer. The two ICDrisk subtypes displayed distinct clinicopathologic features, tumor-infiltrating immune cell patterns, and biological processes. The ISlowmeTNAhigh subtype showed low intratumoral heterogeneity (ITH) and immune-activated phenotypes and correlated with better survival than the other subtypes within the high ICDrisk group. This study suggests effective biomarkers for the prediction of OS in LUAD patients and immunotherapeutic response across Pan-cancer and contributes to enhancing our understanding of intrinsic immunogenic tumor cell death.

Ten-year trends of the clinicopathological characteristics, surgical treatments and survival outcomes of operable lung cancer patients in monocenter: a retrospective cohort study.

Background: Lung cancer is one of the cancers with the highest morbidity and mortality. During the last decade, the trends of clinical characteristics, surgical treatments and survival of lung cancer patients in China have remained unclear. Methods: All lung cancer patients operated on from 2011 to 2020 were identified in a prospectively maintained database of Sun Yat-sen University Cancer Center. Results: A total of 7,800 lung cancer patients were included in this study. Within the past 10 years, the average age at diagnosis of the patients remained stable, the proportion of asymptomatic, female and nonsmoking patients increased, and the average tumor size decreased from 3.766 to 2.300 cm. In addition, the proportion of early stage and adenocarcinoma increased, while that of squamous cell carcinoma decreased. Among the patients, the proportion of patients having video-assisted thoracic surgery increased. More than 80% of the patients underwent lobectomy and systematic nodal dissection over the 10 years. Additionally, both the average postoperative length of stay and 1-, 3-, and 6-month postoperative mortality decreased. Moreover, the 1-, 3-, and 5-year overall survival (OS) rates of all the operable patients increased from 89.8, 73.9, and 63.8% to 99.6, 90.7, and 80.8%, respectively. The 5-year OS rates of the patients with stage I, II, and III lung cancer were 87.6, 79.9, and 59.9%, respectively, which were higher than those in other published data. Conclusion: There were significant changes in the clinicopathological characteristics, surgical treatments and survival outcomes of the patients with operable lung cancer from 2011 to 2020.

The comparison of manual and mechanical anastomosis after total pharyngolaryngoesophagectomy.

Background: Total pharyngolaryngoesophagectomy (TPLE) is considered as a curative treatment for hypopharynx cancer and cervical esophageal carcinomas (HPCECs). Traditional pharyngo-gastric anastomosis is usually performed manually, and postoperative complications are common. The aim of this study was to introduce a new technique for mechanical anastomosis and to evaluate perioperative outcomes and prognosis. Methods: From May 1995 to Nov 2021, a series of 75 consecutive patients who received TPLE for a pathological diagnosis of HPCECs at Sun Yat-sen Memorial Hospital were evaluated. Mechanical anastomosis was performed in 28 cases and manual anastomosis was performed in 47 cases. The data from these patients were retrospectively analyzed. Results: The mean age was 57.6 years, and 20% of the patients were female. The rate of anastomotic fistula and wound infection in the mechanical group were significantly lower than that in the manual group. The operation time, intraoperative blood loss and postoperative hospital stays were significantly higher in the manual group than that in the mechanical group. The R0 resection rate and the tumor characteristics were not significantly different between groups. There was no significant difference in overall survival and disease-free survival between the two groups. Conclusion: The mechanical anastomosis technology adopted by this study was shown to be a safer and more effective procedure with similar survival comparable to that of manual anastomosis for the HPCECs patients.

The Gradual Correction of Adult Severe Rigid Equinus Deformity Using Minimal Invasive U-Osteotomy With Taylor Spatial Frame.

BACKGROUND: U-osteotomy with Taylor Spatial Frame correction is a rarely reported treatment method particularly well-suited for severe rigid equinus deformity in adults. The purpose of this study was to evaluate the effectiveness and efficacy of deformity correction and clinical outcome using this technique. METHODS: We present a retrospective review of 30 feet in 26 patients who received U-osteotomy with Taylor Spatial Frame. Radiologic outcomes were measured using the anterior tibiotalar angle (TTA) with conventional weightbearing radiographs. Functional assessments included American Orthopaedic Foot & Ankle Society (AOFAS) ankle and hindfoot scores and patient satisfaction using Likert scale. RESULTS: The etiology included trauma (9), neglected or relapsed clubfoot (6), spina bifida (5), poliomyelitis (4), Charcot-Marie-Tooth disease (4), and iatrogenic (2). All patients had equinus deformity with TTA more than 140 degrees (median 157.5, 141-177). There were varus deformity in 19 feet, limb length discrepancy in 6 legs, and genu procurvatum deformity in 2 legs. The duration of gradual correction was 53.6±13.5 days (33-73 days), and the external fixation time was 147.8±25.2 days (98-203 days). At last follow-up, TTA in all patients improved significantly (P < .001) to 113.5 degrees (111.8-116.0). All patients had plantigrade feet, except for 2 cases of residual mild equinovarus deformity, 2 cases of residual mild hindfoot varus deformity, 1 case of moderate hindfoot varus recurrence. The AOFAS scores significantly improved (P < .001) from 51.0 points (29.0-66.0) to 76.0 points (69.5-88.0). Eighteen patients were very satisfied, 6 patients were somewhat satisfied, and 2 patients were somewhat dissatisfied. CONCLUSION: Using minimally invasive U-osteotomy with Taylor Spatial Frame to gradually correct the adult severe rigid equinus deformity proved to be an effective and relatively safe method associated with high patient satisfaction rates. LEVEL OF EVIDENCE: Level IV, case series.

A tumor microenvironment gene set-Based prognostic signature for non-small-cell lung cancer.

Background: The tumor microenvironment (TME) is involved in the development and progression of lung carcinomas. A deeper understanding of TME landscape would offer insight into prognostic biomarkers and potential therapeutic targets investigation. To this end, we aimed to identify the TME components of lung cancer and develop a prognostic signature to predict overall survival (OS). Methods: Expression data was retrieved from The Cancer Genome Atlas (TCGA) database and differentially expressed TME-related genes were calculated between tumor and normal tissues. Then nonnegative matrix factorization (NMF) clustering was used to identify two distinct subtypes. Results: Our analysis yielded a gene panel consisting of seven TME-related genes as candidate signature set. With this panel, our model showed that the high-risk group experienced a shorter survival time. This model was further validated by an independent cohort with data from Gene Expression Omnibus (GEO) database (GSE50081 and GSE13213). Additionally, we integrated the clinical factors and risk score to construct a nomogram for predicting prognosis. Our data suggested less immune cells infiltration but more fibroblasts were found in tumor tissues derived from patients at high-risk and those patients exhibited a worse immunotherapy response. Conclusion: The signature set proposed in this work could be an effective model for estimating OS in lung cancer patients. Hopefully analysis of the TME could have the potential to provide novel diagnostic, prognostic and therapeutic opportunities.

CURC: a CUDA-based reference-free read compressor.

MOTIVATION: The data deluge of high-throughput sequencing (HTS) has posed great challenges to data storage and transfer. Many specific compression tools have been developed to solve this problem. However, most of the existing compressors are based on central processing unit (CPU) platform, which might be inefficient and expensive to handle large-scale HTS data. With the popularization of graphics processing units (GPUs), GPU-compatible sequencing data compressors become desirable to exploit the computing power of GPUs. RESULTS: We present a GPU-accelerated reference-free read compressor, namely CURC, for FASTQ files. Under a GPU-CPU heterogeneous parallel scheme, CURC implements highly efficient lossless compression of DNA stream based on the pseudogenome approach and CUDA library. CURC achieves 2-6-fold speedup of the compression with competitive compression rate, compared with other state-of-the-art reference-free read compressors. AVAILABILITY AND IMPLEMENTATION: CURC can be downloaded from https://github.com/BioinfoSZU/CURC. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Spray deposited polycrystalline MAPbBr3 thick films for hole-transport-material free solar cells.

A spray deposition procedure for the fabrication of polycrystalline MAPbBr3 thick films (20-100 µm) is developed and highly efficient (>5.5% under AM1.5 sunlight) hole-transport-material free perovskite solar cells are successfully made with 40 µm thick MAPbBr3 films.

Long noncoding RNA SNHG12 induces proliferation, migration, epithelial-mesenchymal transition, and stemness of esophageal squamous cell carcinoma cells via post-transcriptional regulation of BMI1 and CTNNB1.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors around the world. Numerous studies have revealed the function of long noncoding RNAs (lncRNAs) in cancers, including ESCC. In this study, lncRNA small nucleolar RNA host gene 12 (SNHG12), mainly distributed in ESCC cell cytoplasm, was overexpressed in ESCC specimens and CD133+ cells. In CD133- ESCC cells, SNHG12 overexpression promoted cell proliferation, migration, epithelial-mesenchymal transition (EMT), and stemness and SNHG12 silencing led to opposite results. Furthermore, SNHG12 sequestered miR-6835-3p and induced the proto-oncogene, polycomb ring finger (BMI1). SNHG12 also enhanced the stability of CTNNB1, the mRNA encoding ß-catenin, via recruiting insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) in ESCC. Rescue assays indicated that CTNNB1 and BMI1 were targets for SNHG12 to regulate ESCC cell proliferation, migration, EMT, and stemness. Furthermore, SOX4 (sex-determining region Y-box 4) bound with the SNHG12 promoter to transcriptionally activate SNHG12 in ESCC. Finally, in vivo data showed SNHG12 knockdown retarded tumorigenesis and metastasis in ESCC. In summary, SNHG12 induces proliferation, migration, EMT, and stemness of ESCC cells via post-transcriptional regulation of BMI1 and CTNNB1, indicating that targeting SNHG12 might be a novel target for ESCC treatment.

HIF-1α Promotes the Metastasis of Esophageal Squamous Cell Carcinoma by Targeting SP1.

Background: In microenvironment of malignant tumors, Hypoxia-Inducible Factors (HIF), most importantly HIF-1α, play an important role in regulation of adaptive biological response to hypoxia, promoting angiogenesis and metastasis. However, the underlying mechanism that HIF-1α regulates metastasis needs to be further clarified. Methods: The expressions of HIF-1α and SP1 were detected in 182 samples of esophageal squamous cell carcinoma (ESCC) and adjacent normal tissues by immunohistochemistry (IHC), and the correlation between the expression levels of HIF-1α and SP1 was analyzed. The expression of HIF-1α in ESCC cell lines TE1 and KYSE30 was then detected using qRT-PCR and western blot. The potential binding sites of HIF-1α on the SP1 promoter were analyzed using UCSC and JASPAR databases, verified by chromosomal immunoprecipitation (ChIP) assay and qRT-PCR. The effects of HIF-1α and SP1 on ESCC cell migration and invasion were then tested with Transwell and Matrigel experiments. Results: The expression of HIF-1α in cancer tissues is higher than adjacent normal tissues, and is correlated with metastasis, recurrence and poor prognosis. Upon silencing HIF-1α by siRNA, the invasion and migration ability of ESCC cells were significantly inhibited, which could be restored by the overexpression of SP1. Hypoxic conditions significantly increased the expression of HIF-1α and SP1 at both protein and mRNA levels in ESCC cells. HIF-1α enhanced SP1 transcription through binding to the promoter region. The expression of protein and mRNA levels of SP1 was decreased by silencing HIF-1α in cells. In contrast, overexpression of HIF-1α significantly increased the mRNA and protein levels of SP1. The expression of SP1 in ESCC was positively correlated with the protein expression of HIF-1α and poor prognosis. Conclusion: The results of our study indicate that HIF-1α promotes metastasis of ESCC by targeting SP1 in a hypoxic microenvironment. Further study on this mechanism may elucidate the possibility of HIF-1α and SP1 as new targets for the treatment of ESCC.

Hsa_circ_0006948 enhances cancer progression and epithelial-mesenchymal transition through the miR-490-3p/HMGA2 axis in esophageal squamous cell carcinoma.

Increasing studies have indicated that circular RNAs (circRNAs) are important in cancer progression. However, few circRNAs associated with epithelial-mesenchymal transition (EMT) have been elucidated in esophageal squamous cell carcinoma (ESCC). In this study, we aimed to identify whether hsa_circ_0006948 promotes ESCC cell EMT and explore its biological mechanisms. We first screened circRNA expression profiles using a circRNA microarray, and found that the expression of a novel circRNA, hsa_circ_0006948, is increased in 153 ESCC tissues and cell lines compared with noncancerous tissues and cell lines. Additionally, high hsa_circ_0006948 levels were positively associated with lymphatic metastasis and poor prognosis. Functionally, the assays indicated that cell proliferation, migration and invasion were promoted by hsa_circ_0006948 both in vitro and in vivo. Furthermore, we analyzed the relationship between hsa_circ_0006948 and miR-490-3p through bioinformatics, luciferase reporter assays, RNA immunoprecipitation and qRT-PCR. We found that hsa_circ_0006948 could bind directly to miR-490-3p which targets the 3'UTR of the oncogene HMGA2 to induce EMT. In conclusion, hsa_circ_0006948 was overexpressed in ESCC tissues and promoted cancer progression, and it could induce EMT by enhancing HMGA2 by sponging miR-490-3p, suggesting that hsa_circ_0006948 could be a biomarker for ESCC.

circGSK3ß promotes metastasis in esophageal squamous cell carcinoma by augmenting ß-catenin signaling.

BACKGROUND: Circular RNAs (circRNAs), a novel class of noncoding RNAs, have recently drawn much attention in the pathogenesis of human cancers. However, the role of circRNAs in esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we aimed to identify novel circRNAs that regulate ESCC progression and explored their regulatory mechanisms and clinical significance in ESCC. METHODS: Differentially expressed circRNAs between ESCC and paired adjacent normal tissues were identified using microarrays. The effects of a specific differentially expressed circRNA (circGSK3ß) on tumor progression were explored in vitro and in vivo. Plasma samples from patients with ESCC, benign lesions and healthy controls were subjected to droplet digital PCR (ddPCR) analyses for circGSK3ß, and the detection rates of plasma circGSK3ß for ESCC were investigated. RESULTS: We demonstrated that upregulated expression of circGSK3ß was positively associated with advanced clinical stage and poor outcome in patients with ESCC. We further revealed that circGSK3ß promoted ESCC cell migration and invasion via direct interaction with GSK3ß and inhibiting GSK3ß activity, providing a novel mechanism of circRNA in cancer progression. Importantly, we identified that circGSK3ß expression in plasma was a biomarker for detection of ESCC and early stage of ESCC with the area under curve (AUC) of 0.782 and 0.793, respectively. CONCLUSIONS: CircGSK3ß exerts critical roles in promoting ESCC metastasis and may serve as a novel therapeutic target for ESCC patients. The plasma level of circGSK3ß have potential to serve as a novel diagnostic and prognostic biomarker for ESCC detection.

CCL18-induced HOTAIR upregulation promotes malignant progression in esophageal squamous cell carcinoma through the miR-130a-5p-ZEB1 axis.

Accumulating evidence indicates that CCL18 and the long non-coding RNA, HOTAIR, have critical roles in cancer progression and metastasis, but the correlation between CCL18 and HOTAIR in esophageal squamous cell carcinoma (ESCC) and their downstream molecular mechanisms remain unclear. Overexpression of CCL18 in ESCC tissues was associated with a worse survival in patients with ESCC. CCL18 enhanced the invasiveness of ESCC cells in a dose-dependent manner, whereas CCL18 knockdown inhibited their invasiveness. In particular, CCL18 expression was positively associated with HOTAIR expression in ESCC tissues. Furthermore, CCL18 upregulated the expression of HOTAIR, and knockdown of HOTAIR alleviated the CCL18-induced invasiveness of ESCC cells. HOTAIR may act as a competing endogenous RNA and could effectively becoming a sponge for miR-130a-5p, thereby modulating the derepression of ZEB1 and promoting epithelial-mesenchymal transition in ESCC. Our study suggests that CCL18 contributes to the malignant progression of esophageal cancer by upregulating HOTAIR expression. HOTAIR overexpression may promote tumor invasiveness and progression in ESCC, given that HOTAIR functions as a miR-130a-5p sponge, positively regulating ZEB1. This provides new therapeutic targets for early diagnosis and treatment of ESCC.