CXCL10 impairs synaptic plasticity was modulated by cGAS-STING pathway after stroke in mice.

Sensorimotor deficits following stroke remain a major cause of disability, but little is known about the specific pathological mechanisms. Exploring the pathological mechanisms and identifying potential therapeutic targets to promote functional rehabilitation after stroke are essential. CXCL10, also known as interferon-gamma-inducible protein 10 (IP-10), plays an important role in multiple brain disorders by mediating synaptic plasticity, yet its role in stroke is still unclear. In this study, mice were treated with photothrombotic stroke, and sensorimotor deficits were determined by the ladder walking tests, tape removal tests, and rotarod tests. The density of dendritic spines and synaptic plasticity was evaluated by Thy1-EGFP mice and electrophysiology. We found that photothrombotic stroke induced sensorimotor deficits and upregulated the expression of CXCL10, whereas suppressing the expression of CXCL10 by adeno-associated virus (AAV) ameliorated sensorimotor deficits and increased the levels of synapse-related proteins, the density of dendritic spines and synaptic strength. Furthermore, the cGAS-STING pathway was activated by stroke and induced CXCL10 release, and cGAS or STING antagonists downregulated the levels of CXCL10 and improved synaptic plasticity after stroke. Collectively, our results indicate that cGAS-STING pathway activation promoted CXCL10 release and impaired synaptic plasticity during stroke recovery.

Characteristics of after-discharges following compound muscle action potential or F-wave in primary peripheral nerve hyperexcitability syndrome.

INTRODUCTION/AIMS: F-wave testing frequently reveals after-discharges of varied morphologies in patients with primary peripheral nerve hyperexcitability syndrome (PNHS), although reports are scant. This study aimed to explore the morphological characteristics of the after-discharges during F-wave tests in PNHS, and to assess the association between after-discharges and the disease classification. METHODS: We conducted a retrospective analysis of patients diagnosed with PNHS between 2014 and 2022. The morphological characteristic and duration of after-discharges during F-wave tests were analyzed. After-discharges in the Morvan syndrome group were compared with those in non-Morvan group, and between groups with positive or negative voltage-gated potassium channel (VGKC) complex antibodies. RESULTS: Twenty-nine patients were included in the study, of which 25 exhibited after-discharges. All after-discharges in Morvan patients occurred following compound muscle action potential (CMAP). In non-Morvan patients, after-discharges occurred following F-wave (32%) and CMAP (47%). The durations of after-discharges following CMAP were significantly prolonged in Morvan (54.2 ± 18.8 ms) compared to non-Morvan patients (34.5 ± 15.0 ms). The majority of antibody-positive patients (18/20) exhibited after-discharges following CMAP, whereas 67% of antibody-negative patients (6/9) showed after-discharges following F-wave. DISCUSSION: The varying presentations of after-discharges, including their location (after CMAP or F-wave) and the duration of after-discharge can assist in clinically classifying PNHS.

Treatment of primary progressive aphasia by repetitive transcranial magnetic stimulation: a randomized, double-blind, placebo-controlled study.

To evaluate the efficacy of high-frequency repetitive transcranial magnetic stimulation (rTMS) in patients with primary progressive aphasia (PPA). In this randomized, double-blind trial in a single center, patients who were diagnosed with PPA were randomly assigned to receive either real rTMS or sham rTMS treatment. High-frequency rTMS was delivered to the dorsolateral prefrontal cortex (DLPFC). The primary outcome was the change in Boston Naming Test (BNT) score at each follow-up compared to the baseline. The secondary outcomes included change in CAL (Communicative Activity Log) and WAB (Western Aphasia Battery) compared to baseline and neuropsychological assessments. Forty patients (16 with nonfluent, 12 with semantic and 12 with logopenic variant PPA) were enrolled and randomly assigned to the rTMS or sham rTMS group, with 20 patients in each group. Thirty-five patients (87.5%) completed a 6-month follow-up. Compared to the sham rTMS group, the BNT improvement and WAB improvement in the real rTMS group were significantly higher. These significant improvements could be observed throughout the entire 6-month follow-up. At 1 month and 3 months after treatment, CAL improvements of real rTMS were significantly higher than sham rTMS. The improvements in BNT, CAL and WAB did not significantly differ among PPA variants. No significant improvement in neuropsychological assessments was observed. High-frequency rTMS delivered to DLPFC improved language functions in patients with different PPA variants. The efficacy was still observed after 6 months of treatment. Trial registration: NCT04431401 ( https://clinicaltrials.gov/ct2/show/NCT04431401 ).

The combined effects of overweight/obesity and dietary antioxidant quality score on hypertension in children and adolescents.

BACKGROUND: This study was to evaluate the combined effects of overweight/obesity and DAQS on the risk of hypertension in children and adolescents. METHODS: In this cross-sectional study, the data of 14,316 subjects were extracted from the National Health and Nutrition Examination Survey (NHANES). Multivariate logistic regression analysis was used to explore the associations of obesity and DAQS with the risk of hypertension. The combined effect of overweight/obesity and DAQS on the risk of hypertension was evaluated. RESULTS: Body mass index (BMI)-for-age < 85th percentile was associated with reduced risk of hypertension in children and adolescents [odds ratio (OR) = 0.48, 95% confidence interval (CI): 0.41-0.62]. No significant association between DAQS ≥ 3 and the risk of hypertension before and after the adjustment of confounders (P > 0.05). Subjects with BMI-for-age of < 85th percentile and DAQS < 3 was associated with decreased risk of hypertension (OR = 0.53, 95%CI: 0.35-0.79). People with BMI-for-age of < 85th percentile and DAQS ≥ 3 was correlated with decreased risk of hypertension (OR = 0.52, 95%CI: 0.36-0.74). Subgroup analysis revealed that in subjects aged ≥ 12 years, decreased risk of hypertension was observed in BMI-for-age < 85th percentile and DAQS < 3 group (OR = 0.48, 95%CI: 0.31-0.73) as well as BMI-for-age < 85th percentile and DAQS ≥ 3 group (OR = 0.47, 95%CI: 0.32-0.67). In boys, BMI-for-age < 85th percentile and DAQS < 3 group (OR = 0.45, 95%CI: 0.25-0.81) as well as BMI-for-age < 85th percentile and DAQS ≥ 3 group (OR = 0.40, 95%CI: 0.25-0.65) were correlated with decreased risk of hypertension. CONCLUSION: Overweight/obesity and DAQS had combined effects on the risk of hypertension in children and adolescents, which implied that for children and adolescents with normal weight, to keep normal weight combined with high quality of diet might be recommended.

MicroRNA-506 modulates insulin resistance in human adipocytes by targeting S6K1 and altering the IRS1/PI3K/AKT insulin signaling pathway.

The incidence of obesity has increased rapidly, becoming a worldwide public health issue that involves insulin resistance. A growing number of recent studies have demonstrated that microRNAs play a significant role in controlling the insulin signaling network. For example, miR-506-3p expression has been demonstrated to correlate with insulin sensitivity; however, the underlying mechanism remains unknown. In this study, we found that miR-506-3p enhanced glucose uptake by 2-deoxy-D-glucose uptake assays and regulated the protein expression of key genes involved in the PI3K/AKT insulin signaling pathway including IRS1, PI3K, AKT, and GlUT4. We next predicted ribosomal protein S6 kinase B1 (S6K1) to be a candidate target of miR-506-3p by bioinformatics analysis and confirmed using dual-luciferase assays that miR-506-3p regulated S6K1 expression by binding to its 3'-UTR. Moreover, modulating S6K1 expression counteracted the effects of miR-506-3p on glucose uptake and PI3K/AKT pathway activation. In conclusion, miR-506-3p altered IR in adipocytes by regulating S6K1-mediated PI3K/AKT pathway activation. Taken together, these findings provide novel insights and potential targets for IR therapy.

Peripheral nerve hyperexcitability syndrome: A clinical, electrophysiological, and immunological study.

INTRODUCTION: Peripheral nerve hyperexcitability syndrome (PNHS) is characterized by muscle fasciculations and spasms. Nerve hyperexcitability and after-discharges can be observed in electrophysiological studies. Autoimmune mechanisms play a major role in the pathophysiology of primary PNHS. METHODS: We retrospectively conducted a case-control study recruiting patients with clinical and electrophysiological features of PNHS. Control patients were diagnosed with other neuronal or muscular diseases. Contactin-associated protein2 (CASPR2) and leucine-rich glioma-inactivated1 (LGI1) antibodies were examined. RESULTS: A total of 19 primary PNHS patients and 39 control patients were analyzed. The most common symptoms for the case group were fasciculations (11/19) and muscle spasms (13/19). Case group patients were likely to demonstrate electrodiagnostic findings of nerve hyperexcitability (17/19) and after-discharges in the tibial nerve (19/19). We found high prevalence of CASPR2 (9/19) and LGI1 (6/19) antibodies in the case group. DISCUSSION: Primary PNHS patients were likely to show after-discharges in the tibial nerve. The pathogenesis of PNHS is autoimmune CASPR2 and LGI1 antibodies are possible pathogenic antibodies for primary PNHS.

Nerve ultrasound studies in POEMS syndrome.

INTRODUCTION: The aim of our study was to assess the ultrasonographic features of peripheral nerves in patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome. METHOD: 34 POEMS syndrome patients and 26 healthy control (HC) participants were recruited prospectively. Cross-sectional area (CSA) was measured in nerves of limbs, trunks of brachial plexus, and cervical nerve roots RESULTS: The CSAs were mildly enlarged at the arm segment of median nerve, elbow segment of ulnar nerve and upper trunk, moderately enlarged at the forearm segment of both median and ulnar nerve, upper trunk of brachial plexus, and C6, C7 cervical nerve roots, and markedly enlarged at the arm segment of ulnar nerve, middle and lower trunk of brachial plexus, as well as C5 cervical root. DISCUSSION: The CSAs of upper limb nerves were larger in POEMS syndrome patients than in HCs, and the enlargements were most prominent proximally.

Sensitivity and specificity of single and combined clouds analyses compared with quantitative motor unit potential analysis.

INTRODUCTION: Turns-amplitude, number of small segments (NSS)-activity, and envelope-activity clouds are three methods of electromyography (EMG) interference pattern analysis. Our objective was to evaluate the sensitivity and specificity of each individual cloud analysis and combined clouds analysis to compare with that of quantitative motor unit potential (QMUP) analysis. METHODS: A total of 379 muscles from 100 patients were analyzed by both QMUP and clouds analyses. Calculation of sensitivity and specificity was based on the clinical diagnosis as the "gold standard." RESULTS: For discrimination of abnormal vs normal and neuropathic vs non-neuropathic, combined clouds analysis had greater sensitivity than QMUP analysis and any single cloud analysis, but there were no differences in specificity. For discrimination of myopathic vs non-myopathic, combined clouds analysis and single cloud analysis had greater sensitivity than QMUP analysis, but there were no differences in specificity. DISCUSSION: Combined clouds analysis was superior to QMUP and each single cloud analysis for distinguishing normal, myopathic, and neuropathic muscles.

miRNA profiling in the hippocampus of attention-deficit/hyperactivity disorder rats.

Attention-deficit/hyperactivity disorder (ADHD) is characterized by attention  deficit, hyperactivity, impulsivity, and learning and memory impairment. Although the pathogenesis of learning and memory impairment is still unknown, some studies have suggested an association with hippocampus dysfunction. We aimed to explore the role of miRNAs in the learning and memory impairments observed in ADHD. Differentially expressed hippocampal micro-ribonucleic acids (miRNAs) in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs) were detected on an Illumina HiSeq. 2000 genome analyzer. A total of 25 differentially expressed miRNAs (fold-change ≥ 2 and P-value < 0.05) were identified. The target genes of these differentially expressed miRNAs were predicted using online tools (TargetScan and miRDB). Gene ontology and pathway analysis of the predicted target genes were carried out to assess their putative biological functions. Meanwhile, quantitative real-time PCR was used to validate the HiSeq results, revealing that three miRNAs (miR-1-b, miR-741-3p, and miR-206-3p) were upregulated and four (miR-182, miR-471-5p, miR-183-5p, and miR-211-5p) were downregulated in the SHR group compared with the WKY group. In addition, we confirmed that Dyrk1a is regulated by miR-211-5p. These results help us understand the contribution of miRNAs in the hippocampus to ADHD and provide new insights into the pathogenesis of this condition.

Design Procedure and Fabrication of Reproducible Silicon Vernier Devices for High-Performance Refractive Index Sensing.

In this paper, we propose a generalized procedure for the design of integrated Vernier devices for high performance chemical and biochemical sensing. In particular, we demonstrate the accurate control of the most critical design and fabrication parameters of silicon-on-insulator cascade-coupled racetrack resonators operating in the second regime of the Vernier effect, around 1.55 µm. The experimental implementation of our design strategies has allowed a rigorous and reliable investigation of the influence of racetrack resonator and directional coupler dimensions as well as of waveguide process variability on the operation of Vernier devices. Figures of merit of our Vernier architectures have been measured experimentally, evidencing a high reproducibility and a very good agreement with the theoretical predictions, as also confirmed by relative errors even lower than 1%. Finally, a Vernier gain as high as 30.3, average insertion loss of 2.1 dB and extinction ratio up to 30 dB have been achieved.

Low loss silicon waveguides for the mid-infrared.

Silicon-on-insulator (SOI) has been used as a platform for near-infrared photonic devices for more than twenty years. Longer wavelengths, however, may be problematic for SOI due to higher absorption loss in silicon dioxide. In this paper we report propagation loss measurements for the longest wavelength used so far on SOI platform. We show that propagation losses of 0.6-0.7 dB/cm can be achieved at a wavelength of 3.39 µm. We also report propagation loss measurements for silicon on porous silicon (SiPSi) waveguides at the same wavelength.

Laser erasable implanted gratings for integrated silicon photonics.

In this work we experimentally demonstrate laser erasable germanium implanted Bragg gratings in SOI. Bragg gratings are formed in a silicon waveguide by ion implantation induced amorphization, and are subsequently erased by a contained laser thermal treatment process. An extinction ratio up to 24dB has been demonstrated in transmission for the fabricated implanted Bragg gratings with lengths up to 1000µm. Results are also presented, demonstrating that the gratings can be selectively removed by UV pulsed laser annealing, enabling a new concept of laser erasable devices for integrated photonics.

A prospective study on split-hand index as a biomarker for the diagnosis of amyotrophic lateral sclerosis.

OBJECTIVE: To determine the practical diagnostic utility of split-hand index (SI) values calculated from F-wave persistence (SIFP) and the F/M amplitude ratio (SIF/M) for differentiating patients with amyotrophic lateral sclerosis (ALS) from other conditions. Methods: This prospective study recruited consecutive patients from Peking Union Medical College Hospital, China, between June 2019 and December 2019. Patients 18-80 years old who had clinical neuromuscular symptoms affecting the upper limbs and required electrophysiological examinations to aid diagnosis were eligible. Compound muscle action potentials (CMAPs) and F-waves recorded from the abductor pollicis brevis (APB), first dorsal interosseous muscle (FDI), and abductor digiti minimi (ADM) were examined. SIFP and SIF/M were calculated as: SI = (APB × FDI)/ADM. The sensitivity and specificity of SIFP and SIF/M in differentiating ALS from non-ALS conditions were derived using receiver operating characteristic (ROC) curves. Results: A total of 309 participants, comprising 91 (29.4%) with ALS and 218 (70.6%) with other neuromuscular disorders, were enrolled after 54 were excluded. SIFP was significantly reduced and SIF/M increased in the ALS group compared with the non-ALS group (p < 0.001). By ROC curve analysis, an SIFP cutoff of 73.3 showed 85.7% sensitivity and 80.7% specificity for differentiating ALS from non-ALS. SIF/M and SICMAP showed lower sensitivity (67% and 75.8%, respectively, p < 0.001) than SIFP for ALS diagnosis. SIFP and SIF/M combined did not outperform SIFP alone. Conclusion: SIFP could be a sensitive, noninvasive neurophysiological diagnostic marker for ALS patients with affected upper limbs. In particular, an SIFP value of 73.3 might be the optimal cutoff for diagnosing ALS.

Split-hand index in amyotrophic lateral sclerosis: an F-wave study.

Objective: Split-hand sign is a useful clinical and electrophysiological feature in the diagnosis of amyotrophic lateral sclerosis (ALS). We proposed a novel split-hand index (SI) using F-wave persistence (FP) and assessed its diagnostic utility in ALS. Methods: Eighty-three consecutive ALS patients were recruited, and 50 healthy, age-, and height-matched volunteers were used as a control group. Compound muscle action potentials (CMAP) and FP were recorded from the abductor pollicis brevis (APB), first dorsal interosseous (FDI), and the abductor digiti minimi (ADM) muscles. The SI derived from FP was calculated using the following formula: SIFP = (FPAPB ×FPFDI)/FPADM. The sensitivity and specificity of SIFP and SICMAP in differentiating ALS from healthy controls (HCs) were derived from receiver-operating characteristic (ROC) curve analysis. Results: Both SIFP and SICMAP were significantly reduced in ALS patients. The ROC curve analysis indicated that both SIFP and SICMAP reliably differentiated ALS from HCs [0.92 (95% CI: 0.88-0.95); 0.86 (95% CI: 0.82-0.91)], but SIFP showed better diagnostic accuracy than SICMAP (p = 0.04), with a high sensitivity (81.2%) and specificity (97%). In subgroup analyses, SIFP appeared to be a better variable than SICMAP for differentiation of ALS patients with normal CMAP from HCs, with an area under the curve of 0.87 (95% CI: 0.80-0.93), sensitivity of 69.4%, and specificity of 94%. Conclusion: The SIFP reliably distinguished ALS patients from HCs and may be more sensitive for determining the split-hand pattern of ALS than SICMAP, particularly in the early stage of the disease.

Reassessment of Split-Leg Signs in Amyotrophic Lateral Sclerosis: Differential Involvement of the Extensor Digitorum Brevis and Abductor Hallucis Muscles.

Background: The muscle patterns involved in the "split-leg" syndrome of amyotrophic lateral sclerosis (ALS) remains controversial. We sought to evaluate and reassess the pattern of the extensor digitorum brevis (EDB) and the abductor hallucis (AH) muscles' involvement in split-leg syndrome in ALS. Methods: We recruited 60 consecutive patients with ALS and 25 healthy controls (HCs). Compound muscle action potentials (CMAPs) and F-waves were recorded over the EDB and AH muscles in all subjects. For comparison, we classified patients into two categories based on the presence or absence of lower limbs symptoms. Results: The EDB/AH CMAP amplitude ratio was significantly reduced in patients with affected legs (0.33 ± 0.21, P = 0.007), whereas patients with unaffected legs had a ratio similar to that of the HCs. The EDB/AH ratios for the F-wave latencies, mean F-wave amplitude, mean F/M amplitude ratio, and the persistence of the total repeater F-wave shapes (index Freps) of the EDB-AH, were significantly increased in the affected leg group, whereas the EDB/AH ratio for F-wave persistence was significantly reduced. These findings indicated a greater loss of lower motor neurons (LMNs) innervating the EDB and dysfunction of spinal motoneurons innervating the EDB. In the unaffected leg group, the EDB, but not the AH, F-wave latencies, mean and maximal F/M amplitude ratios, and index Freps were significantly altered. Receiver operating characteristic curve analysis suggested that the EDB F-wave latencies, mean F/M amplitude ratios, and index Freqs (area under the curve [AUC] > 0.8) more strongly differentiated patients with ALS from the HCs compared to the EDB/AH CMAP amplitude ratio (AUC = 0.61). Notably, the EDB maximal F-wave latency and index Freqs reliably differentiated patients with unaffected legs (HCs), with AUCs of 0.83 (95% CI 0.76-0.91) and 0.81 (95% CI 0.72-0.89), sensitivities of 76 and 78%, and specificities of 76 and 78%, respectively. Conclusions: These results suggest preferential EDB compared to AH involvement in the split-leg syndrome of ALS. The EDB maximal F-wave latency and index Freqs robustly differentiated patients with ALS from HCs, which might facilitate an earlier identification of ALS.

Serum levels of trace elements in children born after assisted reproductive technology.

INTRODUCTION: The health and development of newborn children born via assisted reproductive technology (ART), as well as their health in adulthood, have raised great concern. This study was designed to investigate whether ART children have differences in the levels of trace elements compared with naturally conceived children. METHODS: This study included those ART children and controls aged 1 to 12 years assessed with a follow-up protocol. Serum levels of the trace elements zinc, copper, iron, calcium, magnesium and lead were determined and analyzed. RESULTS: There were no significant differences in age, gender or body weight between the ART and control groups. There were no significant differences in the rates of deficiency or excess of trace elements between the two groups. Serum lead levels in children born via ART were significantly higher than those in the controls, whereas the levels of zinc and iron were significantly decreased in the ART group, although these levels were still within the normal ranges. DISCUSSION: These results indicate the need to monitor the blood levels of zinc, iron and lead in ART children aged 1-6 years old. These findings contribute to our understanding on the long-term safety of ART and may facilitate screening for potential diseases related to trace elements.

Mutation analysis of KIF5A in Chinese amyotrophic lateral sclerosis patients.

Amyotrophic lateral sclerosis (ALS) is an age-related fatal neurodegenerative orphan disorder that is characterized by progressive injury of both the upper and lower motor neurons. Recently, loss-of-function mutations predominately disrupting the C-terminal amino acid sequence of KIF5A via aberrant exon 27 splicing have been reported in European ALS cohorts. However, the contributions of KIF5A mutations in Asian patients with ALS remain unclear. KIF5A sequences, including exons 26 and 27, were analyzed in a large Chinese ALS cohort comprising 33 unrelated familial ALS probands, 645 sporadic ALS (SALS) patients, 15 ALS patients presenting with concomitant frontotemporal dementia, 400 in-house controls, and 12,951 East Asian individuals from the Exome Aggregation Consortium and Genome Aggregation Database databases. As a result, the previously reported canonical splicing site mutation c.2993-1G>A was found in 1 SALS patient, while no mutations were detected in familial ALS case or ALS patients presenting with concomitant frontotemporal dementia. The frequency of KIF5A mutations accounts for 0.16% (1/645) of Chinese SALS patients, implying that it is an uncommon genetic determinant of ALS in Chinese patients.

Mechanism hypotheses for the electrophysiological manifestations of two cases of endplate acetylcholinesterase deficiency related congenital myasthenic syndrome.

OBJECTIVE: To summarize the electrophysiological characteristics of two cases of endplate acetylcholinesterase deficiency (EAD) related congenital myasthenic syndrome (CMS) caused by COLQ mutation and to discuss the possible mechanism of these electrophysiological phenomena. METHODS: Electrophysiological examinations were conducted including nerve conduction studies, routine electromyography (EMG), repetitive nerve stimulation (RNS) and single fiber EMG (SFEMG). The ulnar nerve was also stimulated at 50 Hz followed by 0.5 Hz to record the recovery process of compound muscle action potential (CMAP). RESULTS: Repetitive CMAP (R-CMAP) was found in motor nerve conduction in both cases. Needle EMG showed myogenic damages and SFEMG showed remarkably increased jitter values. Of note, the amplitude of CMAP and R-CMAP showed regular changing trends, and so did their time intervals in RNS studies. CONCLUSIONS: The change patterns of CMAP and R-CMAP, in combination with other electrophysiological features are very useful for the diagnosis of EAD related CMS, especially in predicting the presence of correct gene mutations.

Creatine kinase level and its relationship with quantitative electromyographic characteristics in amyotrophic lateral sclerosis.

OBJECTIVE: To explore the relationship between serum creatine kinase (CK) level and electromyographic characteristics in patients with amyotrophic lateral sclerosis (ALS). METHODS: Two hundred thirty-eight consecutive ALS patients were enrolled. All patients underwent electrophysiological study with a consistent approach. We calculated a compound muscle action potential (CMAP) sum score, and spontaneous potentials were graded from 0 to 4 depending on their density and distribution. We tested for any independent correlation of the CK levels with CMAP sum score, mean spontaneous potential (MSP) score, F wave persistence or conduction velocity. RESULTS: The median serum CK level was 151 U/L. Log CK was independently correlated with MSP score (ß = 0.07, 95% CI: 0.01-0.14, p = 0.032) and F persistence (ß = -0.0013, 95% CI: -0.00251 to -0.0002, p = 0.02) but not with CMAP sum score or F wave conduction velocity. When stratified by sex, the correlation of log CK with MSP score and F persistence was significant in male but not female patients. CONCLUSIONS: The results support that lower motor neuron loss and muscle denervation are associated with elevated CK levels of ALS patients. SIGNIFICANCE: The severity of lower motor neuron loss and denervation might be involved in pathophysiological mechanisms of CK elevation in ALS patients.

MicroRNA-1 inhibits tumorigenicity of esophageal squamous cell carcinoma and enhances sensitivity to gefitinib.

Dysregulation of microRNAs in various types of human cancer promote or suppress oncogenesis. MicroRNA (miR)-1 was previously revealed to function as a tumor suppressor in prostate cancer cells, and its expression was associated with reduced metastatic potential in lung cancer. The present study investigated the role of miR-1 and its association with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) in the pathophysiology of esophageal squamous cell carcinoma (ESCC), and analyzed the effects of miR-1 inhibitor or mimics on sensitivity to epidermal growth factor receptor-tyrosine kinase inhibitors, the alterations of cell cycle distribution and apoptosis in ESCC cells. Compared with normal tissues, the level of miR-1 expression was significantly lower and PIK3CA expression was higher in ESCC tissues. The level of miR-1 expression was also inversely associated with the level of PIK3CA mRNA expression. Low miR-1 and high PIK3CA expression levels were strongly associated with lymph node metastasis, and the level of miR-1 expression was negatively associated with clinical Tumor-Node-Metastasis stage. Furthermore, exogenous expression of miR-1 inhibited growth, arrested cell cycle in the G1 phase and increased apoptosis in ESCC cells, whereas it decreased PIK3CA protein expression levels. Furthermore, overexpression of miR-1 increased the sensitivity of ESCC cells to the anticancer drug, gefitinib. A possible mechanism for this increased sensitivity to gefitinib may be inactivation of the PIK3CA signaling pathway. To the best of our knowledge, this is the first time that the results of the present study demonstrated that miR-1 upregulation may be a potential strategy for the treatment of human ESCC.