Posterior division of ipsilateral C7 transfer to C5 for shoulder abduction limitation.

Background: Reparation of C5 by proximal selective ipsilateral C7 transfer has been reported for the treatment of neurogenic shoulder abduction limitation as an alternative to the reparation of the suprascapular nerve (SSN) and the axillary nerve (AXN) by distal nerve transfers. However, there is a lack of evidence to support either strategy leading to better outcomes based on long-term follow-up. Objective: The purpose of the study was to investigate the safety and long-term outcomes of the posterior division of ipsilateral C7 (PDIC7) transfer to C5 in treating neurogenic shoulder abduction limitation. Methods: A total of 27 cases with limited shoulder abduction caused by C5 injury (24 cases of trauma, 2 cases of neuritis, and 1 case of iatrogenic injury) underwent PDIC7 transfer to the C5 root. A total of 12 cases (11 cases of trauma and 1 case of neuritis) of C5 injury underwent spinal accessory nerve (SAN) transfer to SSN plus the triceps muscular branch of the radial nerve (TMBRN) transfer to AXN. The patients were followed up for at least 12 months for muscle strength and shoulder abduction range of motion (ROM). Results: In cases that underwent PDIC7 transfer, the average shoulder abduction was 105.9° at the 12-month follow-up. In total, 26 of 27 patients recovered at least M3 (13 reached M4) (Medical Research Council Grading) of the deltoid. In cases that underwent SAN transfer to SSN plus TMBRN to AXN, the average shoulder abduction was 84.6° at the 12-month follow-up. In total, 11 of 12 patients recovered at least M3 (4 reached M4) of the deltoid. Conclusion: Posterior division of ipsilateral C7 transfer is a one-stage, safe, and effective surgical procedure for patients with neurogenic shoulder abduction limitation.

Ablation of NLRP3 inflammasome attenuates muscle atrophy via inhibiting pyroptosis, proteolysis and apoptosis following denervation.

Rationale: The inflammasome has been widely reported to be involved in various myopathies, but little is known about its role in denervated muscle. Here, we explored the role of NLRP3 inflammasome activation in experimental models of denervation in vitro and in vivo. Methods: Employing muscular NLRP3 specific knock-out (NLRP3 cKO) mice, we evaluated the effects of the NLRP3 inflammasome on muscle atrophy in vivo in muscle-specific NLRP3 conditional knockout (cKO) mice subjected to sciatic nerve transection and in vitro in cells incubated with NLRP3 inflammasome activator (NIA). To evaluate the underlying mechanisms, samples were collected at different time points for RNA-sequencing (RNA-seq), and the interacting molecules were comprehensively analysed. Results : In the experimental model, NLRP3 inflammasome activation after denervation led to pyroptosis and upregulation of MuRF1 and Atrogin-1 expression, facilitating ubiquitin-proteasome system (UPS) activation, which was responsible for muscle proteolysis. Conversely, genetic knockout of NLRP3 in muscle inhibited pyroptosis-associated protein expression and significantly ameliorated muscle atrophy. Furthermore, cotreatment with shRNA-NLRP3 markedly attenuated NIA-induced C2C12 myotube pyroptosis and atrophy. Intriguingly, inhibition of NLRP3 inflammasome activation significantly suppressed apoptosis. Conclusions: These in vivo and in vitro findings demonstrate that during denervation, the NLRP3 inflammasome is activated and stimulates muscle atrophy via pyroptosis, proteolysis and apoptosis, suggesting that it may contribute to the pathogenesis of neuromuscular diseases.

EID3 Promotes Glioma Cell Proliferation and Survival by Inactivating AMPKα1.

OBJECTIVE: EID3 (EP300-interacting inhibitor of differentiation) was identified as a novel member of EID family and plays a pivotal role in colorectal cancer development. However, its role in glioma remained elusive. In current study, we identified EID3 as a novel oncogenic molecule in human glioma and is critical for glioma cell survival, proliferation and invasion. METHODS: A total of five patients with glioma were recruited in present study and fresh glioma samples were removed from patients. Four weeks old male non-obese diabetic severe combined immune deficiency (NOD/SCID) mice were used as transplant recipient models. The subcutaneous tumor size was calculated and recorded every week with vernier caliper. EID3 and AMP-activated protein kinase α1 (AMPKα1) expression levels were confirmed by real-time polymerase chain reaction and Western blot assays. Colony formation assays were performed to evaluate cell proliferation. Methyl thiazolyl tetrazolium (MTT) assays were performed for cell viability assessment. Trypan blue staining approach was applied for cell death assessment. Cell Apoptosis DNA ELISA Detection Kit was used for apoptosis assessment. RESULTS: EID3 was preferentially expressed in glioma tissues/cells, while undetectable in astrocytes, neuronal cells, or normal brain tissues. EID3 knocking down significantly hindered glioma cell proliferation and invasion, as well as induced reduction of cell viability, apoptosis and cell death. EID3 knocking down also greatly inhibited tumor growth in SCID mice. Knocking down of AMPKα1 could effectively rescue glioma cells from apoptosis and cell death caused by EID3 absence, indicating that AMPKα1 acted as a key downstream regulator of EID3 and mediated suppression effects caused by EID3 knocking down inhibition. These findings were confirmed in glioma cells generated patient-derived xenograft models. AMPKα1 protein levels were affected by MG132 treatment in glioma, which suggested EID3 might down regulate AMPKα1 through protein degradation. CONCLUSION: Collectively, our study demonstrated that EID3 promoted glioma cell proliferation and survival by inhibiting AMPKα1 expression. Targeting EID3 might represent a promising strategy for treating glioma.

ROS-activated CXCR2+ neutrophils recruited by CXCL1 delay denervated skeletal muscle atrophy and undergo P53-mediated apoptosis.

Neutrophils are the earliest master inflammatory regulator cells recruited to target tissues after direct infection or injury. Although inflammatory factors are present in muscle that has been indirectly disturbed by peripheral nerve injury, whether neutrophils are present and play a role in the associated inflammatory process remains unclear. Here, intravital imaging analysis using spinning-disk confocal intravital microscopy was employed to dynamically identify neutrophils in denervated muscle. Slice digital scanning and 3D-view reconstruction analyses demonstrated that neutrophils escape from vessels and migrate into denervated muscle tissue. Analyses using reactive oxygen species (ROS) inhibitors and flow cytometry demonstrated that enhanced ROS activate neutrophils after denervation. Transcriptome analysis revealed that the vast majority of neutrophils in denervated muscle were of the CXCR2 subtype and were recruited by CXCL1. Most of these cells gradually disappeared within 1 week via P53-mediated apoptosis. Experiments using specific blockers confirmed that neutrophils slow the process of denervated muscle atrophy. Collectively, these results indicate that activated neutrophils are recruited via chemotaxis to muscle tissue that has been indirectly damaged by denervation, where they function in delaying atrophy.

Molecular feature of neutrophils in immune microenvironment of muscle atrophy.

Homeostasis in skeletal muscle is sustained by the balance of functional and physical interactions between muscle and myofibre microenvironment. Various factors, such as ageing, disuse and denervation, tip the balance and induce skeletal muscle atrophy. Skeletal muscle atrophy, which involves complex physiological and biochemical changes, is accompanied by adverse outcomes and even increased mortality. Multiple studies have investigated the role of neutrophils in atrophied skeletal muscles; however, neutrophil intrusion in muscle is still a polemical knot. As technical obstacles have been overcome, people have gradually discovered new functions of neutrophils. The classical view of neutrophils is no longer applicable to their biological characteristics. To date, no clear association between the hidden injurious effect of neutrophil intrusion and muscle atrophy has been convincingly proven. Throughout this review, we have discussed the neutrophil activities that mediate muscle atrophy for distinct disease occurrences. Hopefully, this review will help both clinicians and researchers of skeletal muscle atrophy with relevant targets to further explore efficient medical interventions and treatments.

Oxidative stress-induced premature senescence and aggravated denervated skeletal muscular atrophy by regulating progerin-p53 interaction.

BACKGROUND: Progerin elevates atrophic gene expression and helps modify the nuclear membrane to cause severe muscle pathology, which is similar to muscle weakness in the elderly, to alter the development and function of the skeletal muscles. Stress-induced premature senescence (SIPS), a state of cell growth arrest owing to such stimuli as oxidation, can be caused by progerin. However, evidence for whether SIPS-induced progerin accumulation is connected to denervation-induced muscle atrophy is not sufficient. METHODS: Flow cytometry and a reactive oxygen species (ROS) as well as inducible nitric oxide synthase (iNOS) inhibitors were used to assess the effect of oxidation on protein (p53), progerin, and nuclear progerin-p53 interaction in the denervated muscles of models of mice suffering from sciatic injury. Loss-of-function approach with the targeted deletion of p53 was used to assess connection among SIPS, denervated muscle atrophy, and fibrogenesis. RESULTS: The augmentation of ROS and iNOS-derived NO in the denervated muscles of models of mice suffering from sciatic injury upregulates p53 and progerin. The abnormal accumulation of progerin in the nuclear membrane as well as the activation of nuclear progerin-p53 interaction triggered premature senescence in the denervated muscle cells of mice. The p53-dependent SIPS in denervated muscles contributes to their atrophy and fibrogenesis. CONCLUSION: Oxidative stress-triggered premature senescence via nuclear progerin-p53 interaction that promotes denervated skeletal muscular atrophy and fibrogenesis.

Aesthetical and Accuracy Outcomes of Reconstruction of Maxillary Defect by 3D Virtual Surgical Planning.

BACKGROUND: Reconstruction of maxillary defect resulting from trauma or oncology surgery is of great importance for patients with physical and psychological complications. The virtual surgical planning (VSP) and 3D printing technics had been used in recent years which simplified the surgical procedure and promoted success and accuracy. To assess the accuracy and outcome of VSP surgery, here we report our experience in maxillary reconstruction retrospectively. METHOD: Patients who received maxillary defect reconstruction from 2013 to 2020 were analyzed retrospectively. These patients were divided into two groups. Group 1 received VSP and 3D printed guiding plates in the surgery, while group 2 underwent free-hand surgery (FHS). Patients with different vertical and horizontal defects were classified according to Brown and Shaw classification. Clinical information and postoperative complications of all patients were collected. For patients with unilateral maxillary defect, orbit volume, orbit height, and the contour of the reconstructed side were compared with the normal side. RESULT: Thirty-four patients who achieved the criteria were analyzed, of which 20 patients underwent VSP surgery. There were primary and secondary reconstruction cases in both two groups. Vascularized iliac crest flap was used in three cases, and fibula flap was performed in the other cases. One flap collapse occurred in FHS group. Seven patients in VSP group received dental implants, while the number in FHS group was 0. In vertical class III cases, the differences in orbit height (ΔD) and orbit volume (ΔV) between normal side and reconstructed side were measured and compared in the two groups. The mean ΔD is 1.78 ± 1.33 mm in VSP group and 4.25 ± 0.95 mm in FHS group, while the mean ΔV is 2.04 ± 0.85 cm3 in VSP group and 3.25 ± 0.17 cm3 in FHS group. The alterations of orbit height and volume in VSP group were much smaller than that in FHS group with statistical significance. From the perspective of aesthetics, the color-gradient map indicates a more symmetric and smoother curve of post-operation appearance in VSP group. CONCLUSION: Compared with traditional free-hand surgical technics, VSP and 3D printing guiding plates can allow for a more accurate maxillary reconstruction with improved aesthetics.

Research progress in immune microenvironment regulation of muscle atrophy induced by peripheral nerve injury.

Denervated skeletal muscular atrophy is primarily characterized by loss of muscle strength and mass and an unideal functional recovery of the muscle after extended denervation. This review emphasizes the interaction between the immune system and the denervated skeletal muscle. Immune cells such as neutrophils, macrophages and T-cells are activated and migrate to denervated muscle, where they release a high concentration of cytokines and chemokines. The migration of these immune cells, the transformation of different functional immune cell subtypes, and the cytokine network in the immune microenvironment may be involved in the regulatory process of muscle atrophy or repair. However, the exact mechanisms of the interaction between these immune cells and immune molecules in skeletal muscles are unclear. In this paper, the immune microenvironment regulation of muscle atrophy induced by peripheral nerve injury is reviewed.

Neferine promotes the apoptosis of HNSCC through the accumulation of p62/SQSTM1 caused by autophagic flux inhibition.

Head and neck squamous cell carcinoma (HNSCC), one of the most common malignancies worldwide, often has a poor prognosis due to the associated metastasis and chemoresistance. Hence, the development of more effective chemotherapeutics is critical. Neferine, a bisbenzylisoquinoline alkaloid isolated from the seed embryo of Nelumbo nucifera (common name: Lotus), exerts antitumor effects by regulating apoptosis and autophagy pathways, making it a potential therapeutic option for HNSCC. In our study, it was revealed that neferine inhibited the growth and induced the apoptosis of HNSCC cells both in vitro and in vivo. Furthermore, the results revealed that neferine activated the ASK1/JNK pathway by increasing reactive oxygen species production, resulting in the subsequent induction of apoptosis and the regulation of canonical autophagy in HNSCC cells. Moreover, a novel pro­apoptotic mechanism was described for neferine via the activation of caspase­8 following the accumulation of p62, which was caused by autophagic flux inhibition. These findings provided insights into the mechanisms responsible for the anticancer effect of neferine, specifically highlighting the crosstalk that occured between apoptosis and autophagy, which was mediated by p62 in HNSCC. Hence, the neferine­induced inhibition of autophagic flux may serve as the basis for a potential adjuvant therapy for HNSCC.

High expression of Rab31 confers a poor prognosis and enhances cell proliferation and invasion in oral squamous cell carcinoma.

Dysregulation of Rab proteins has been observed in various types of cancer. Ectopic expression of Rab31, a member of the Rab protein family, is involved in cancer development and progression. However, the specific role and potential molecular mechanism underlying the functions of Rab31 remain largely unknown. Therefore, the current study aimed to investigate the functions of Rab31 in the development of cancer. Human oral squamous cell carcinoma (OSCC) samples were examined to determine the expression profile of Rab31 and its association with the clinicopathological characteristics of patients with OSCC. Knockdown of Rab31 expression with short hairpin RNA was performed to analyze the functions of Rab31 in vitro and in vivo. The expression of Rab31 was significantly elevated in human OSCC samples compared with that in normal oral mucosal epithelial tissues, and high expression levels were associated with high pathological grades. Furthermore, positive expression of Rab31 was associated with a poor prognosis in patients with OSCC. In addition, knockdown of Rab31 expression suppressed OSCC cell proliferation and induced apoptosis compared with those in the control­transfected cells, which may have been caused by downregulated cyclin D1 and survivin expression and upregulated B­cell lymphoma 2 expression. The invasive ability of OSCC cells was also abrogated by Rab31 silencing compared with that in the control­transfected cells, which was associated with downregulated N­cadherin and matrix metalloproteinase­9 expression levels and upregulated levels of E­cadherin expression. Furthermore, silencing Rab31 in OSCC cell lines, when compared with the control­transfected cells, significantly reduced tumor growth and inhibited the expression of survivin, Ki­67 and N­cadherin in vivo. By contrast, the expression levels of E­cadherin were increased. Taken together, the results of the present study supported important roles for Rab31 in regulating OSCC cell proliferation, apoptosis and invasion and may facilitate the identification of a new therapeutic target for the treatment of OSCC.

Denervation-Related Neuromuscular Junction Changes: From Degeneration to Regeneration.

Neuromuscular junctions (NMJs) are the key interface between terminal nerves and targeted muscle, which undergo degeneration during denervation periods. Denervation-related NMJs changes limits the recovery level of nerve repair strategies. Insights into mechanisms behind neuromuscular junction degeneration and regeneration, following denervation and reinnervation, are of clinical value. Developing some therapies to maintain or protect structures and functions of NMJs may contribute to a better prognosis. Here, we reviewed previous studies of NMJs focusing on the morphological, functional, and molecular changes after denervation, and if those changes can be reversed after reinnervation. Also, we reviewed about the present probable strategies that have been applied clinically or could still be studied in targeting the neuromuscular junction protection or regeneration improvement.

Contralateral obturator nerve transfer for femoral nerve restoration: a case report.

BACKGROUND: Femoral nerve injury may occur in severe traffic accident injuries with pelvic fracture. Sural nerve grafts or ipsilateral obturator nerve transfer may be used to restore femoral nerve function. We report a new procedure transferring the contralateral obturator nerve to restore femoral nerve function. CASE DESCRIPTION: A 30 year-old male suffering complete lumbar plexus rapture received a contralateral obturator nerve transfer in our hospital. At 2 years follow up he had gained Medical Research Council Grade 3 muscle strength in his 23th months follow-up, with normal gait, Lower Extremity Functional Scale score of 58.75% and Femoral Nerve Motor Function Scale score 61%. CONCLUSION: The contralateral obturator nerve transfer is a reliable alternative if the nerve graft or ipsilateral obturator nerve cannot be performed.

Ficus carica L. Attenuates Denervated Skeletal Muscle Atrophy via PPARα/NF-κB Pathway.

Treatment options for denervated skeletal muscle atrophy are limited, in part because the underlying molecular mechanisms are not well understood. Unlike previous transcriptomics studies conducted in rodent models of peripheral nerve injury, in the present study, we performed high-throughput sequencing with denervated atrophic biceps muscle and normal (non-denervated) sternocleidomastoid muscle samples obtained from four brachial plexus injury (BPI) patients. We also investigated whether Ficus carica L. (FCL.) extract can suppress denervated muscle atrophy in a mouse model, along with the mechanism of action. We identified 1471 genes that were differentially expressed between clinical specimens of atrophic and normal muscle, including 771 that were downregulated and 700 that were upregulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the differentially expressed genes were mainly enriched in the GO terms "structural constituent of muscle," "Z disc," "M band," and "striated muscle contraction," as well as "Cell adhesion molecules," "Glycolysis/Gluconeogenesis," "Peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway," and "P53 signaling pathway." In experiments using mice, the reduction in wet weight and myofiber diameter in denervated muscle was improved by FCL. extract compared to saline administration, which was accompanied by downregulation of the proinflammatory cytokines interleukin (IL)-1ß and IL-6. Moreover, although both denervated groups showed increased nuclear factor (NF)-κB activation and PPARα expression, the degree of NF-κB activation was lower while PPARα and inhibitor of NF-κB IκBα expression was higher in FCL. extract-treated mice. Thus, FCL. extract suppresses denervation-induced inflammation and attenuates muscle atrophy by enhancing PPARα expression and inhibiting NF-κB activation. These findings suggest that FCL. extract has therapeutic potential for preventing denervation-induced muscle atrophy caused by peripheral nerve injury or disease.

Different Surgical Reconstructions for Femoral Nerve Injury: A Clinical Study on 9 Cases.

BACKGROUND: Femoral nerve palsy can cause loss in quadriceps function and knee extension disability, which may lead to severe lower extremity impairment. The obturator nerve trunk transfer in the pelvic, the obturator nerve mortal branches transfer out of the pelvic, along with nerve graft, was introduced years ago to restore femoral nerve function. However, the outcomes of these procedures have never been compared. The aims of this study were to give our experiences in surgical reconstruction for femoral nerve injury and to compare the outcomes of different approaches. METHODS: Nine patients with complete femoral nerve injury have been enrolled in this study between March 2012 and July 2016. All patients were followed up for at least 2 years after surgical intervention for sural nerve graft (n = 3), obturator trunk transfer in the pelvic (n = 2), or obturator nerve mortal branches transfer out of the pelvic (n = 4). RESULTS: All patients gained satisfactory quadriceps Medical Research Council grade (M3-M4+) after more than 2 years of follow-up. The sural nerve graft led to the earliest recovery on average, followed by obturator nerve mortal branches transfer in the thigh level and then obturator nerve trunk transfer in the pelvic. The functional outcomes, demonstrated by Lower Extremity Functional Scale and Femoral Nerve Motor Function Scale scores, also showed that the sural nerve graft was the best on average, followed by obturator nerve trunk transfer in the pelvic and then obturator nerve mortal branches transfer in the thigh level. CONCLUSIONS: Our results indicate that all these 3 procedures are safe and reliable ways to reconstruct femoral nerve function and can be applied to patients with different kinds of injuries. The sural nerve graft should be considered in the first place and the obturator nerve transfer at different level (trunk transfer in the pelvic or mortal branches transfer out of the pelvic) can be performed as the alternative.

Experimental Study of Nerve Transfer to Restore Diaphragm Function.

BACKGROUND: Diaphragmatic paralysis after phrenic nerve injury is an infrequent but serious condition. The destruction of respiratory function after unilateral phrenic nerve injury has been the subject of many investigations. METHODS: In this study, we used a rat model of complete paralysis of the unilateral diaphragm to observe changes in pulmonary function. RESULTS: We found in young rats with complete paralysis of the unilateral diaphragm, the vital capacity and total lung capacity show compensation after 4 weeks, and contralateral phrenic nerve transfer can enhance pulmonary function. However, in the aged rats, respiratory function parameters do not show compensation until 16 weeks after injury. CONCLUSIONS: These findings suggest that contralateral phrenic nerve end-to-side anastomosis is a promising therapeutic strategy. In general, our results suggest that this surgical method may hold great potential to be a secure, feasible, and effective technique to rescue diaphragmatic function.

Contralateral C7 transfer via both ulnar nerve and medial antebrachial cutaneous nerve to repair total brachial plexus avulsion: a preliminary report.

Aim: After brachial plexus injuries, sacrifice of the contralateral C7 (cC7) root from the non-injured side is well tolerated and various schemes to innervate the injured side from the cC7 root have been used. Objective: To demonstrate the surgical outcomes from transferring the cC7 to the affected side via both the ulnar nerve and medial antebrachial cutaneous nerve (MACN).Methods: A retrospective study of 16 adult patients sustaining total brachial plexus avulsion who underwent this procedure. The British Medical Research Council (MRC) grading system and the disabilities of the arm, shoulder, and hand (DASH) questionnaire scoring were used to evaluate the recovery.Results: About 68.75% of the patients achieved functional recovery of elbow flexion to M3 or better and 43.75% achieved motor recovery of wrist and finger flexion to M3 or better. Sensation in the median nerve territory recovered to S2 or better in 68.75%. The DASH scores after surgery were significantly lower than those before surgery.Conclusions: cC7 transfer via both ulnar and MACNs is an effective and safe procedure in patients sustaining total injuries of brachial plexus.

Prognostic implications of decreased microRNA-101-3p expression in patients with non-small cell lung cancer.

To investigate the expression level of microRNA-101-3p (miR-101-3p) and its possible association with progression, prognosis and chemotherapy in patients with non-small cell lung cancer (NSCLC), the Gene Expression Omnibus (GEO) database was used. Quantitative polymerase chain reaction was used to verify the expression in 327 NSCLC and 42 adjacent normal lung tissues, of which 42 viable tissues were paired with nearby normal lung tissues. Based on the Cox regression model, univariate and multivariate analyses were used to address the factors that had effects on overall survival (OS) and disease-free survival (DFS) rate. Data from the GEO database demonstrated that the miR-101-3p expression in NSCLC was downregulated, compared with normal lung cancer. Survival analysis through univariate and multivariate models indicated that the miR-101-3p expression level was a crucial risk factor for OS and DFS in patients with NSCLC. A number of clinical parameters were determined to be associated with miR-101-3p expression, including tumor diameter, lymph node metastasis and tumor-node-metastasis stage. Adjuvant chemotherapy with high expression of miR-101-3p was determined to increase OS and DFS in patients with NSCLC, compared with patients with de novo or low expression of miR-101-3p. The present results demonstrated that miR-101-3p expression levels were associated with NSCLC progression and prognosis, which indicated that miR-101-3p may serve as a biomarker for patients with NSCLC who have received adjuvant chemotherapy.

Downregulation of miR-223 and miR-19a induces differentiation and promotes recruitment of osteoclast cells in giant-cell tumor of the bone via the Runx2/TWIST-RANK/RANKL pathway.

Giant-cell tumor (GCT) of the bone is an invasiveness and high recurrent bone tumor that is considered borderline or potentially malignant. To explore the molecular mechanism leading to bone destruction and identify novel targets for treatment, we conducted silencing of miR-223 and miR-19a in stromal giant cells and identified TWIST and Runx2 as their target genes. We investigated the impact of these microRNAs and their target genes on stromal giant cells that promote the differentiation of monocyte/macrophages into osteoclast cells and recruitment to the bone microenvironment, which in turn enhances the bone destruction capacity of GCT. MiR-223 and miR-19a were found to regulate the expression of TWIST and Runx2, influence the RANKL-RANK pathway and the expression of MCP-1, and finally regulate the pathophysiological process of osteolytic bone destruction. Our results indicate that re-expression of miR-223 and miR-19a induces an inhibitory effect on the bone destruction capacity of GCT, suggesting that re-expression of miR-223 and miR-19a can be a novel strategy for the treatment of GCT.

Tumor suppressive microRNA-124a inhibits stemness and enhances gefitinib sensitivity of non-small cell lung cancer cells by targeting ubiquitin-specific protease 14.

Increasing evidence has shown that microRNAs (miRNAs) play a significant functional role by directly regulating respective targets in cancer stem cell (CSC)-induced non-small cell lung cancer (NSCLC) progression and resistance to therapy. In this study, we found that hsa-miR-124a was downregulated during spheroid formation of the NSCLC cell lines SPC-A1 and NCI-H1650 and NSCLC tissues compared with normal lung cells and tissues. Patients with lower hsa-miR-124a expression had shorter overall survival (OS) and progression free survival (PFS). Moreover, ubiquitin-specific protease 14 (USP14) was confirmed to be a direct target of hsa-miR-124a. Furthermore, concomitant low hsa-miR-124a expression and high USP14 expression were correlated with a shorter median OS and PFS in NSCLC patients. Cellular functional analysis verified that the tumor suppressor hsa-miR-124a negatively regulated cell growth and self-renewal, and promoted apoptosis and gefitinib sensitivity of lung cancer stem cells by suppressing its target gene USP14. Our results provide the first evidence that USP14 is a direct target of hsa-miR-124a, and that hsa-miR-124a inhibits stemness and enhances the gefitinib sensitivity of NSCLC cells by targeting USP14. Thus, hsa-miR-124a and USP14 may be useful as tumor biomarkers for the diagnosis and treatment of NSCLC.