Role and mechanism of NCAPD3 in promoting malignant behaviors in gastric cancer.

Background: Gastric cancer (GC) is one of the major malignancies threatening human lives and health. Non-SMC condensin II complex subunit D3 (NCAPD3) plays a crucial role in the occurrence of many diseases. However, its role in GC remains unexplored. Materials and Methods: The Cancer Genome Atlas (TCGA) database, clinical samples, and cell lines were used to analyze NCAPD3 expression in GC. NCAPD3 was overexpressed and inhibited by lentiviral vectors and the CRISPR/Cas9 system, respectively. The biological functions of NCAPD3 were investigated in vitro and in vivo. Gene microarray, Gene set enrichment analysis (GSEA) and ingenuity pathway analysis (IPA) were performed to establish the potential mechanisms. Results: NCAPD3 was highly expressed in GC and was associated with a poor prognosis. NCAPD3 upregulation significantly promoted the malignant biological behaviors of gastric cancer cell, while NCAPD3 inhibition exerted a opposite effect. NCAPD3 loss can directly inhibit CCND1 and ESR1 expression to downregulate the expression of downstream targets CDK6 and IRS1 and inhibit the proliferation of gastric cancer cells. Moreover, NCAPD3 loss activates IRF7 and DDIT3 to regulate apoptosis in gastric cancer cells. Conclusion: Our study revealed that NCAPD3 silencing attenuates malignant phenotypes of GC and that it is a potential target for GC treatment.

Knockdown of NCAPD3 inhibits the tumorigenesis of non-small cell lung cancer by regulation of the PI3K/Akt pathway.

BACKGROUND: Accumulating evidence indicates that aberrant non-SMC condensin II complex subunit D3 (NCAPD3) is associated with carcinogenesis of various cancers. Nevertheless, the biological role of NCAPD3 in the pathogenesis of non-small cell lung cancer (NSCLC) remains unclear. METHODS: Immunohistochemistry and Western blot were performed to assess NCAPD3 expression in NSCLC tissues and cell lines. The ability of cell proliferation, invasion, and migration was evaluated by CCK-8 assays, EdU assays, Transwell assays, and scratch wound healing assays. Flow cytometry was performed to verify the cell cycle and apoptosis. RNA-sequence and rescue experiment were performed to reveal the underlying mechanisms. RESULTS: The results showed that the expression of NCAPD3 was significantly elevated in NSCLC tissues. High NCAPD3 expression in NSCLC patients was substantially associated with a worse prognosis. Functionally, knockdown of NCAPD3 resulted in cell apoptosis and cell cycle arrest in NSCLC cells as well as a significant inhibition of proliferation, invasion, and migration. Furthermore, RNA-sequencing analysis suggested that NCAPD3 contributes to NSCLC carcinogenesis by regulating PI3K/Akt/FOXO4 pathway. Insulin-like growth factors-1 (IGF-1), an activator of PI3K/Akt signaling pathway, could reverse NCAPD3 silence-mediated proliferation inhibition and apoptosis in NSCLC cells. CONCLUSION: NCAPD3 suppresses apoptosis and promotes cell proliferation via the PI3K/Akt/FOXO4 signaling pathway, suggesting a potential use for NCAPD3 inhibitors as NSCLC therapeutics.

Association of interleukin-6, ferritin, and lactate dehydrogenase with venous thromboembolism in COVID-19: a systematic review and meta-analysis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is frequntly accompanied by venous thromboembolism (VTE), and its mechanism may be related to the abnormal inflammation and immune status of COVID-19 patients. It has been proved that interleukin-6 (IL-6), ferritin and lactate dehydrogenase (LDH) may play an important role in the occurrence of VTE in COVID-19 infection. But whether they can server as predictors for VTE in COVID-19 is still unclear. In this study, we performed a systematic review and meta-analysis to compare IL-6, ferritin and LDH in VTE and non-VTE COVID-19 patients in order to shed light on the prevention and treatment of VTE. METHODS: Related literatures were searched in PubMed, Embase, Web of Science, Google Scholar, China National Knowledge Infrastructure (CNKI), WANGFANG. COVID-19 patients were divided into VTE group and non-VTE group. Meta-analysis was then conducted to compare levels of IL-6, ferritin and LDH between the two groups. RESULTS: We finally included and analyzed 17 literatures from January 2019 to October 2022. There was a total of 7,035 COVID-19 patients, with a weighted mean age of 60.01 years. Males accounted for 62.64% and 61.34% patients were in intensive care unit (ICU). Weighted mean difference (WMD) of IL-6, ferritin and LDH was 31.15 (95% CI: 9.82, 52.49), 257.02 (95% CI: 51.70, 462.33) and 41.79 (95% CI: -19.38, 102.96), respectively. The above results indicated that than compared with non-VTE group, VTE group had significantly higher levels of IL-6 and ferritin but similar LDH. CONCLUSION: This systematic review and meta-analysis pointed out that elevated levels of IL-6 and ferritin were significantly possitive associated with VTE, thus could be used as biological predictive indicators of VTE among COVID-19 patients. However, no association was found between level of LDH and VTE. Therefore, close monitoring of changes in IL-6 and ferritin concentrations is of great value in assisting clinicans to rapidly identify thrombotic complications among COVID-19 patients, hence facilitating the timely effective managment. Further studies are required in terms of the clinical role of cytokines in the occurrence of VTE among COVID-19 infection, with more reliable systematic controls and interventional trials.

Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma.

BACKGROUND: Microsatellite instability-high (MSI-H) is a unique genomic status in many cancers. However, its role in the genomic features and immunotherapy in cholangiocarcinoma (CCA) is unclear. This study aimed to systematically investigate the genomic characterization and immunotherapy efficacy of MSI-H patients with CCA. METHODS: We enrolled 887 patients with CCA in this study. Tumor samples were collected for next-generation sequencing. Differences in genomic alterations between the MSI-H and microsatellite stability (MSS) groups were analyzed. We also investigated the survival of PD-1 inhibitor-based immunotherapy between two groups of 139 patients with advanced CCA. RESULTS: Differential genetic alterations between the MSI-H and MSS groups included mutations in ARID1A, ACVR2A, TGFBR2, KMT2D, RNF43, and PBRM1 which were enriched in MSI-H groups. Patients with an MSI-H status have a significantly higher tumor mutation burden (TMB) (median 41.7 vs. 3.1 muts/Mb, P < 0.001) and more positive programmed death ligand 1 (PD-L1) expression (37.5% vs. 11.9%, P < 0.001) than those with an MSS status. Among patients receiving PD-1 inhibitor-based therapy, those with MSI-H had a longer median overall survival (OS, hazard ratio (HR) = 0.17, P = 0.001) and progression-free survival (PFS, HR = 0.14, P < 0.001) than patients with MSS. Integrating MSI-H and PD-L1 expression status (combined positive score ≥ 5) could distinguish the efficacy of immunotherapy. CONCLUSIONS: MSI-H status was associated with a higher TMB value and more positive PD-L1 expression in CCA tumors. Moreover, in patients with advanced CCA who received PD-1 inhibitor-based immunotherapy, MSI-H and positive PD-L1 expression were associated with improved both OS and PFS. TRIAL REGISTRATION: This study was registered on ClinicalTrials.gov on 07/01/2017 (NCT03892577).

Single-cell RNA sequencing in cancer research: discovering novel biomarkers and therapeutic targets for immune checkpoint blockade.

Immune checkpoint blockade (ICB) has become a promising strategy in treating advanced cancers, providing significant survival benefits for patients with various cancer types. However, among the vast population of cancer patients, only a small fraction are able to respond to and derive benefits from ICB therapy. Numerous factors contribute to the diminished efficacy of ICB, with the complex tumor microenvironment (TME) playing an important role. Therefore, comprehensively understanding the intricate composition of the TME is critical for elucidating the mechanisms that underlie distinct responses to ICB in patients. Single-cell RNA sequencing (scRNA-seq) is a novel technique that reveals gene expression profiles of individual cells, facilitating the investigation of TME heterogeneity at a high resolution and the identification of key cell subsets participating in the response to ICB. This review emphasizes the importance of scRNA-seq in studying ICB and summarizes recent findings in the discovery of biomarkers that predict ICB response and novel potential therapeutic targets for immunotherapy. These findings suggest future directions for the clinical implementation of cancer immunotherapy, facilitating further advancements in precision medicine.

Case report: Clinical management of recurrent small cell lung cancer transformation complicated with lung cancer-induced acute pancreatitis after lung adenocarcinoma surgery.

In the diagnosis and treatment of non-small cell lung cancer (NSCLC), the histological type may change from lung adenocarcinoma to lung squamous cell cancer or small cell lung cancer (SCLC). Pancreatic metastasis is extremely rare in advanced lung cancer, and pancreatitis characterized by lung cancer metastasis-induced acute pancreatitis (MIAP) is more rare. This paper reports in detail the clinical diagnosis and treatment of a female patient with lung adenocarcinoma who relapsed after radical surgery and progressed after multiple treatments. A second pathological biopsy revealed SCLC transformation, and the patient developed pancreatic metastasis and lung cancer MIAP during follow-up treatment. This paper mainly suggests that clinicians should pay attention to the possibility of pathological type transformation in the progression of advanced NSCLC, closely observe the dynamic changes of tumor markers and pay attention to the re-biopsy pathological analysis. In addition, it provides clinical experience and scientific reference for the discovery, diagnosis and treatment of transforming SCLC and lung cancer MIAP.

The role of HMGB1 in digestive cancer.

High mobility group box protein B1 (HMGB1) belongs to the HMG family, is widely expressed in the nucleus of digestive mucosal epithelial cells, mesenchymal cells and immune cells, and binds to DNA to participate in genomic structural stability, mismatch repair and transcriptional regulation to maintain normal cellular activities. In the context of digestive inflammation and tumors, HMGB1 readily migrates into the extracellular matrix and binds to immune cell receptors to affect their function and differentiation, further promoting digestive tract tissue injury and tumor development. Notably, HMGB1 can also promote the antitumor immune response. Therefore, these seemingly opposing effects in tumors make targeted HMGB1 therapies important in digestive cancer. This review focuses on the role of HMGB1 in tumors and its effects on key pathways of digestive cancer and aims to provide new possibilities for targeted tumor therapy.

Clinical features and prognosis of advanced intra- and extra-pulmonary neuroendocrine carcinomas.

Objective: We examined the clinical features and prognosis of advanced intra- and extra-pulmonary neuroendocrine carcinomas (NECs) to offer additional guidance for the clinical treatment of small-cell lung cancer (SCLC), which is a type of advanced intrapulmonary NEC (IPNECs). Materials and Methods: The clinical data and survival of 123 patients with advanced IPNECs and extrapulmonary NECs (EPNECs) were obtained. We retrospectively examined the corresponding clinical diagnosis and treatment and investigated the significant factors influencing the survival prognosis of patients with NECs. Results: There were 90 cases of IPNECs (including 81 cases of SCLC), and 33 cases of EPNECs. The median overall survival (OS) of IPNECs was significantly longer than that of the EPNECs in the gastrointestinal tract and in the other regions (P < 0.05). The median OS of patients with other IPNECs was longer than that of patients with SCLC (P > 0.05). Multivariate analysis demonstrated that age, liver metastasis, number of cycles of first-line chemotherapy, and chest radiotherapy were risk factors influencing OS in patients with NECs (P < 0.05). Conclusions: The survival of IPNECs was significantly longer than that of EPNECs in the gastrointestinal tract and other regions. Nevertheless, patients with advanced NECs who were older and had liver metastases had a poorer prognosis. Multidisciplinary treatments including multicycle chemotherapy and a combination of chemotherapy and radiotherapy should function significantly in extending the survival of NECs.

Construction of lung cancer serum markers based on ReliefF feature selection.

Serum miRNAs are available clinical samples for cancer screening. Identifying early serum markers in lung cancer (LC) is essential for patients' early diagnosis and clinical treatment. Expression data of serum miRNAs of lung adenocarcinoma (LUAD) patients and healthy individuals were downloaded from the Gene Expression Omnibus (GEO). These data were normalized and subjected to differential expression analysis to obtain differentially expressed miRNAs (DEmiRNAs). The DEmiRNAs were subsequently subjected to ReliefF feature selection, and subsets closely related to cancer were screened as candidate feature miRNAs. Thereafter, a Gaussian Naive Bayes (NB), Support Vector Machine (SVM), and Random Forest (RF) classifier were constructed based on these candidate feature miRNAs. Then the best diagnostic signature was constructed through NB combined with incremental feature selection (IFS). Thereafter, these samples were subjected to principal component analysis (PCA) based on miRNAs with optimal predictive performance. Finally, the peripheral serum miRNAs of 64 LUAD patients and 59 normal individuals were extracted for qRT-PCR analysis to validate the performance of the diagnostic model in respect of clinical detection. Finally, according to area under the curve (AUC) and accuracy values, the NB classifier composed of miR-5100 and miR-663a manifested the most outstanding diagnostic performance. The PCA results also revealed that the 2-miRNA diagnostic signature could effectively distinguish cancer patients from healthy individuals. Finally, qRT-PCR results of clinical serum samples revealed that miR-5100 and miR-663a expression in tumor samples was remarkably higher than that in normal samples. The AUC of the 2-miRNA diagnostic signature was 0.968. In summary, we identified markers (miR-5100 and miR-663a) in serum for early LUAD screening, providing ideas for developing early LUAD diagnostic models.

Exposure to phthalate increases the risk of eczema in children: Findings from a systematic review and meta-analysis.

Emerging evidence indicated phthalate exposure might raise the risk of eczema in children. However, these findings were inconsistent. The relation between phthalate exposure and childhood eczema remained debated. Therefore, we performed this meta-analysis to assess their association. PubMed, Web of Science, and Embase were searched for eligible studies. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated for risk estimate. Thirty studies involving 12,615 participants were included in this meta-analysis. For prenatal phthalate exposure assessed with maternal samples, the pooled results showed gestational exposure to monobenzyl phthalate (MBzP) (OR: 1.17, 95% CI: 1.00-1.36), but not the other phthalates, was correlated with increased risk of eczema in children. For childhood exposure assessed using children's urine sample, our pooled results indicated that postnatal exposure to MBzP (OR: 1.10, 95% CI: 1.02-1.19), mono-2-ethyl-5-hydroxyhexyl phthalate (MEHHP) (OR: 1.32, 95% CI: 1.08-1.61), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) (OR: 1.24, 95% CI: 1.06-1.44), and molar summation of di-2-ethylhexyl phthalate (DEHP) (OR: 1.23, 95% CI: 1.06-1.42) were associated with higher risk of eczema. While for studies using household dust to estimate environmental phthalate exposure and eczema risk, the pooled results showed no significant association. Subgroup analyses indicated study country, diagnostic mode, and children's age contributed to the heterogeneity. The results of our meta-analysis demonstrated that phthalate exposure during both prenatal and postnatal periods was associated with elevated risk of eczema in children. However, such association was not strong as the pooled ORs were relatively small. Further studies are warranted to verify these findings and explore the underlying mechanism.

Thyroid Dysfunction in Non-Small Cell Lung Cancer With Immune Checkpoint Inhibitors: A Meta-Analysis.

Immune checkpoint inhibitors (ICIs) have been established as the cornerstone for advanced non-small cell lung cancer, while thyroid adverse events (AEs) associated with ICIs have not been systematically documented. Therefore, we performed a meta-analysis to evaluate the effect of ICI applications on the thyroid of patients with non-small cell lung cancer. We performed a systematic search of PubMed, the Cochrane Library, Web of Science, and Embase for eligible randomized controlled trials up to December 2021. Clinical trials reporting thyroid AEs including hypothyroidism, hyperthyroidism, and thyroiditis were enrolled. The I2  statistic was also calculated to quantify the heterogeneity. Data were evaluated as risk ratio (RR) and corresponding 95%CIs. A total of 10 randomized clinical trials involving 6154 patients were included in this meta-analysis. ICI application was found to have a statistically significant higher risk of all grade hypothyroidism (RR, 7.03; P < 0.0001), hyperthyroidism (RR, 4.88; P < 0.0001), and thyroiditis (RR, 6.58; P = 0.0014) compared with the chemotherapy group. Moreover, we demonstrated that second-line therapy significantly increased the risk of all-grade hypothyroidism (RR, 7.03 [95%CI, 4.69-10.55]) and hyperthyroidism (RR, 4.88 [95%CI, 3.11-7.65]). Our meta-analysis manifested that regimens with ICIs may significantly increase all grades of hypothyroidism, hyperthyroidism, and thyroiditis. ICIs may induce the occurrence and exacerbation of endocrine AEs compared with chemotherapy.

Risk factors and prognostic factors for pulmonary large cell neuroendocrine carcinoma with brain metastasis.

BACKGROUND: As the studies regarding the brain metastasis (BM) of pulmonary large cell neuroendocrine carcinoma (LCNEC) are insufficient, the present research aims to describe the risk factors and prognostic factors that are related to cancer-specific survival (CSS) for LCNEC patients with BM. METHODS: The data of LCNEC patients between January 2010 and October 2018 were obtained from the SEER database. Binary logistic regression analyses were utilized to screen the possible risk factors related to BM. Prognostic factors for LCNEC patients with BM were indentified by Cox regression analyses. Moreover, a nomogram was established to predict the 6-, 12-, and 18-month CSS rates. The concordance index (C-index), receiver operating characteristic (ROC) curves and calibration curves were utilized to assess the discrimination and reliability of the model. Clinical decision curves (DCAs) were used to evaluate the clinical benefits and utility of our model. RESULTS: Totally, 1875 patients were enrolled, with 294 (15.7%) of them having BM at diagnosis. Multivariate logistic regression analyses revealed that patients with age < 65 (odds ratio, OR = 1.564) and N2 staging (OR = 1.775) had a greater chance of developing BM. Age (≥ 65 vs. < 65: hazard ratio, HR = 1.409), T staging (T1 vs. T0: HR = 4.580; T2 vs. T0: HR = 6.008; T3 vs. T0: HR = 7.065; T4 vs. T0: HR = 6.821), N staging (N2 vs. N0: HR = 1.592; N3 vs. N0: HR = 1.654), liver metastasis (HR = 1.410), primary site surgery (HR = 0.581) and chemotherapy (HR = 0.452) were independent prognostic factors for LCNEC patients with BM. A nomogram prediction model was constructed by incorporating these factors. Using the C-index, calibration curves, ROC curves, and DCAs, we found that the clinical prediction model performed well. CONCLUSION: We described the risk factors and prognostic factors that were associated with CSS for LCNEC patients with BM. The related nomogram was established and validated to help clinicians formulate more rational and effective treatment strategies.

Efficacy of immune checkpoint inhibitors plus molecular targeted agents after the progression of lenvatinib for advanced hepatocellular carcinoma.

Background: Lenvatinib is a standard first-line systemic therapy in advanced hepatocellular carcinoma (aHCC) and is widely used in all lines. However, the efficacy and safety of immune checkpoint inhibitors (ICIs) plus molecular targeted agents (MTAs) after the progression of lenvatinib treatment are unclear. Objective: The aim of this study was to evaluate the anticancer effects of ICI plus MTA in patients with aHCC who progressed after lenvatinib. Methods: We retrospectively included aHCC patients treated with ICI plus MTA after the progression of lenvatinib from two medical centers. Participants who continued lenvatinib treatment were classified into the "ICI+Lenva" group, while the "ICI+Others" group included patients receiving other MTAs. The efficacy endpoints were progression-free survival (PFS), post-progression survival (PPS), overall survival (OS), and tumor response following RECIST v1.1. Safety was evaluated according to Common Terminology Criteria for Adverse Events v5.0. Results: In this study, 85 eligible aHCC patients were enrolled, including 58 in the ICI+Lenva group and 27 in the ICI+Others group. At a median follow-up time of 22.8 months, the median PPS and PFS were 14.0 (95% CI: 9.0-18.2) and 4.5 months (95% CI: 3.5-8.3), respectively. The objective response and disease control rates were 10.6% and 52.9%, respectively. No significant differences were observed in any of the efficacy endpoints between the two groups. Prolonged PPS was associated with Child-Pugh grade A, AFP < 400 IU/ml, and concomitant locoregional treatment. All patients experienced adverse events (AEs), but no fatal AEs were observed. Conclusion: ICI plus MTA in aHCC patients after the progression of lenvatinib presented high antitumor activity and safety. Patients could continue lenvatinib treatment and receive ICIs as well as locoregional treatment to achieve better OS.

Prognostic analysis of patients with combined hepatocellular-cholangiocarcinoma after radical resection: A retrospective multicenter cohort study.

BACKGROUND: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a form of rare primary liver cancer that combines intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma. AIM: To investigate overall survival (OS) and recurrence-free survival (RFS) after radical resection in patients with cHCC-CCA, and the clinicopathological factors affecting prognosis in two center hospitals of China. METHODS: We reviewed consecutive patients with cHCC-CCA who received radical resection between January 2005 and September 2021 at Peking Union Medical College and the 5th Medical Center of the PLA General Hospital retrospectively. Regular follow-up and clinicopathological characteristics were systematic collected for baseline and prognostic analysis. RESULTS: Our study included 95 patients who received radical resection. The majority of these patients were male and 82.7% of these patients were infected with HBV. The mean tumor size was 4.5 cm, and approximately 40% of patients had more than one lesion. The median OS was 26.8 (95%CI: 18.5-43.0) mo, and the median RFS was 7.27 (95%CI: 5.83-10.3) mo. Independent predictors of OS were CA19-9 ≥ 37 U/mL (HR = 8.68, P = 0.002), Child-Pugh score > 5 (HR = 5.52, P = 0.027), tumor number > 1 (HR = 30.85, P = 0.002), tumor size and transarterial chemoembolization (TACE) after surgery (HR = 0.2, P = 0.005). CONCLUSION: The overall postoperative survival of cHCC-CCA patients is poor, and most patients experience relapse within a short period of time after surgery. Preoperative tumor biomarker (CA19-9, alpha-fetoprotein) levels, tumor size, and Child-Pugh score can significantly affect OS. Adjuvant TACE after surgery prolongs RFS, suggesting that TACE is a possible option for postoperative adjuvant therapy in patients with cHCC-CCA.

Isolated crater-like tumour in a renal transplant recipient.

Compared with asymptomatic pulmonary cryptococcosis, secondary cutaneous cryptococcosis may be the first clinical manifestation of disseminated infection but it can be difficult to diagnose clinically. The clinical manifestation of cutaneous cryptococcosis is not pathognomonic, varying from nodules to ulcers and plaques, and frequently mimics other pathologies. This case highlights that an isolated tumour can be an initial manifestation of systemic cryptococcosis in a kidney transplant patient.

The Therapeutic Effects of Dihydroartemisinin on Cisplatin-Resistant Gastric Cancer Cells.

BACKGROUND: Dihydroartemisinin (DHA) exhibited anti-tumor effect in a variety of cancer cells, but its mechanism of action is unclear. OBJECTIVES: To investigate the therapeutic effects of DHA on Cisplatin (DDP)-resistant gastric cancer cell strain SGC7901/DDP and the possible molecular mechanism. METHODS: Cells were treated with DHA in a dose- and time-dependent manner, after which their proliferation, apoptosis, invasion, and migration abilities were evaluated. We further evaluated autophagy with mRFP-GFP-LC3 adenovirus transfection and transmission electron microscopy and also detected the expression levels of proteins (related to autophagy and apoptosis) via western blot. Meanwhile, the influence of DHA on cisplatin resistance was detected through a sensitization test and the evaluation of P-gp expression levels. RESULTS: DHA effectively inhibited the proliferation, invasion, and migration of SGC7901/DDP cells and induced cell apoptosis which was accompanied by caspase-8/9/3 activation. Furthermore, exposure to DHA resulted in a pronounced increase in autophagy proteins, including Beclin-1 and LC3 II with PI3K/AKT/mTOR pathway inhibition. Additionally, enhancement of cisplatin sensitivity occurred in SGC7901/DDP cells treated with DHA, which was accompanied by P-gp downregulation. CONCLUSION: DHA exerts an anti-cancer effect on SGC7901/DDP cells and the mechanisms possibly include enhancement of autophagy via PI3K/AKT/mTOR inhibition, inducement of apoptosis through caspase-dependent and mitochondrial pathway, and enhancement of cisplatin sensitivity through P-gp inhibition.

ARHGAP10 inhibits the epithelial-mesenchymal transition of non-small cell lung cancer by inactivating PI3K/Akt/GSK3ß signaling pathway.

BACKGROUND: Rho GTPase activating protein 10 (ARHGAP10) has been implicated as an essential element in multiple cellular process, including cell migration, adhesion and actin cytoskeleton dynamic reorganization. However, the correlation of ARHGAP10 expression with epithelial-mesenchymal transition (EMT) in lung cancer cells is unclear and remains to be elucidated. Herein, we investigated the relationship between the trait of ARHGAP10 and non-small cell lung cancer (NSCLC) pathological process. METHODS: Immunohistochemistry was conducted to evaluate the expression of ARHGAP10 in NSCLC tissues. CCK-8 assays, Transwell assays, scratch assays were applied to assess cell proliferation, invasion and migration. The expression levels of EMT biomarkers and active molecules involved in PI3K/Akt/GSK3ß signaling pathway were examined through immunofluorescence and Western blot. RESULTS: ARHGAP10 was detected to be lower expression in NSCLC tissues compared with normal tissues from individuals. Moreover, overexpression of ARHGAP10 inhibited migratory and invasive potentials of A549 and NCI-H1299 cells. In addition, ARHGAP10 directly mediated the process of EMT via PI3K/Akt/GSK3ß pathway. Meanwhile, activation of the signaling pathway of insulin-like growth factors-1 (IGF-1) reversed ARHGAP10 overexpression regulated EMT in NSCLC cells. CONCLUSION: ARHGAP10 inhibits the epithelial-mesenchymal transition in NSCLC via PI3K/Akt/GSK3ß signaling pathway, suggesting agonist of ARHGAP10 may be an optional remedy for NSCLC patients than traditional opioids.

ADP ribosylation factor guanylate kinase 1 promotes the malignant phenotype of gastric cancer by regulating focal adhesion kinase activation.

AIMS: ADP ribosylation factor guanylate kinase 1 (ASAP1), a phospholipid-dependent guanosine triphosphate (GTP)ase activating protein, has been reported to be involved in the development of various malignant tumors. However, the biological function of ASAP1 in gastric cancer (GC) remains unclear. This study was to investigate its effect and the underlying mechanism for the malignant phenotype of GC. MATERIALS AND METHODS: The Cell Counting Kit-8 assay, flow cytometry, Transwell invasion assay, and wound-healing assay were used to assess the malignant biological behavior of GC cells with ASAP1 overexpression and knockdown. In addition, co-immunoprecipitation was used to analyze the interaction between ASAP1 and FAK in BGC823 cells, and western blotting was used to determine the effects of overexpression and knockdown of ASAP1 on FAK activity in BGC823 cells. Subsequently, functional recovery experiments were used to observe the effect of ASAP1 and FAK on the malignant phenotype of GC cells. KEY FINDINGS: ASAP1 overexpression strongly promoted the malignant biological behavior of SGC7901 cells. Knockdown of ASAP1 effectively weakened the malignant biological behavior of SGC7901 and BGC823 cells. ASAP1 directly interacted with FAK to potentiate FAK activation. In addition, knockdown of FAK combined with ASAP1 overexpression significantly weakened the malignant biological behavior of GC cells, whereas overexpression of FAK combined with knockdown of ASAP1 significantly enhanced the malignant biological behavior of GC cells. SIGNIFICANCE: ASAP1 interacted with FAK, and ASAP1 promoted the malignant phenotype of GC cells by regulating FAK activity. The specific underlying mechanism is worth further investigation.

miR-202-3p negatively regulates MMP-1 to inhibit the proliferation, migration and invasion of lung adenocarcinoma cells.

Lung adenocarcinoma (LUAD) is one of the common cancers. Studies show that MMP-1 is involved in tumor progression, yet relevant regulatory mechanism in LUAD remains to be further elucidated. Here, we demonstrated from bioinformatics analysis for GEO data that MMP-1 was differentially up-regulated in LUAD. miR-202-3p, identified as the upstream regulator of MMP-1 by both bioinformatics and dual-luciferase assays, was differentially down-regulated in LUAD and presented a negative correlation with MMP-1. Following cell biological experiments proved that knocking down the expression of MMP-1 inhibited the proliferation, migration and invasion of LUAD cells, while overexpressed miR-202-3p posed a similar suppressive effect on cancer progression. Additionally, rescue assay further identified that overexpression of MMP-1 attenuated the suppressive effect of up-regulated miR-202-3p on malignant progression of LUAD cells. In all, this research suggests a mechanism by which MMP-1 under the regulation of miR-202-3p modulates the proliferation, migration and invasion of LUAD cells, which may contribute to the development of new therapeutic strategies.