Downregulated CDK10 promotes cancer progression and radioresistance in lung cancer through activating the JNK/c-Jun signaling pathway.

Lung cancer is one of the most significant malignancies, with both high morbidity and mortality. CDK10 is closely related to cancer progression and metastasis. However, its role in lung cancer radioresistance demands further clarification. In this study, we demonstrated that CDK10 was downregulated in lung cancer tissues, and CDK10 expression level was associated with the clinical prognosis in lung cancer patients. We also found that silencing CDK10 promoted lung cancer cell proliferation, migration, and radioresistance. We further verified that silencing CDK10 facilitated the activation of JNK/c-Jun signaling, and c-Jun depletion could reverse the effects of CDK10 knockdown in lung cancer cells. Our findings revealed that CDK10 plays an important role in cell growth and radioresistance by inhibiting JNK/c-Jun signaling pathway in lung cancer. Therefore, CDK10 might be a promising therapeutic target in lung cancer.

Roles of USP9X in cellular functions and tumorigenesis (Review).

Ubiquitin-specific peptidase 9X (USP9X) is involved in certain human diseases, including malignancies, atherosclerosis and certain diseases of the nervous system. USP9X promotes the deubiquitination and stabilization of diverse substrates, thereby exerting a versatile range of effects on pathological and physiological processes. USP9X serves vital roles in the processes of cell survival, invasion and migration in various types of cancer. The present review aims to highlight the current knowledge of USP9X in terms of its structure and the possible mediatory mechanisms involved in certain types of cancer, providing a thorough introduction to its biological functions in carcinogenesis and further outlining its oncogenic or suppressive properties in a diverse range of cancer types. Finally, several perspectives regarding USP9X-targeted pharmacological therapeutics in cancer development are discussed.

Aumolertinib in NSCLC with leptomeningeal involvement, harbouring concurrent EGFR exon 19 deletion and TP53 comutation: a case report.

Background: Aumolertinib (HS-10296), a 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has been shown to have efficacy in treating tumors harboring EGFR sensitive mutations: EGFR in-frame deletions or insertions within exon 19 deletion (19Del) and the exon 21 L858R mutation and EGFR T790M resistance mutation. Research has shown that tumor protein p53 (TP53) mutations and leptomeningeal metastases (LM) are associated with reduced responsiveness and a poor prognosis in patients with advanced non-small cell lung cancer (NSCLC) who have received targeted therapy with EGFR-TKIs. The TP53 mutation is a common concomitant mutation of EGFR amplification in solid tumors. First-line aumolertinib treatment is effective in EGFR concurrent mutated NSCLC, however, the efficacy and survival outcomes in these patients with leptomeningeal metastasis remain unknown. Case Description: We retrospectively examined the data of a lung adenocarcinoma patient, 51 years old, male, multi-mutations of EGFR and TP53, who received 1st-line treatment with a 1st-generation TKI followed by 2nd-line treatment with aumolertinib. Before the 1st-line treatment, the patient underwent a lung biopsy to examine the 520 genes of all cancers using illumia high-throughput sequencing. The sequencing results showed that the patient had the EGFR 19del (p.Leu747_Thr751del)/TP53 (p.lys120fs)/EGFR amplified multiple mutation with a low tumor mutational burden. The patient was treated with gefitinib and achieved progression-free survival (PFS) for 10 months until secondary malignancy of the lymph nodes. The first-generation TKI combined with chemotherapy was applied and then the patient was diagnosed with leptomeningeal metastases. Subsequently, the patient was treated with aumolertinib for 12 months without disease progression. The efficacy evaluation was partial response (PR) with grade 2 rash. Adenocarcinoma cells were found in the cerebrospinal fluid (CSF). CSF-derived circulating tumor deoxyribonucleic acid was detected using the target area probe capture and 2nd-generation high-throughput sequencing technology. The CSF gene detection showed the EGFR p. L747_T751 del, TP53 p. K120fs and EGFR amplification mutations. Conclusions: This is the first reported case in which aumolertinib was used to treat a patient with the multi-mutations of EGFR 19Del, TP53, and EGFR amplification and leptomeningeal metastases. The findings suggested that almonertinib may result in long-period clinical improvement and tolerable safety in concurrent mutated LM NSCLC.

Roles of Cadherin2 in Thyroid Cancer.

Background: The majority of drug-resistant cells in Thyroid cancer (THCA) tend to exhibit an Epithelial mesenchymal transition (EMT) phenotype, and abnormal expression of the cell adhesion molecule Cadherin2 (CDH2) is a hallmark of EMT. However, the roles of CDH2 in THCA and its underlying mechanisms are unknown. Methods: We analyzed the CDH2 expression in The Cancer Genome Atlas (TCGA) database and screened for genes positively associated with CDH2. Small interfering RNA and cell transfection were used for knocking down CDH2 in THCA cells, cell counting kit-8 (CCK-8) assay and immunofluorescence to detect cell proliferation. Binding miRNAs of CDH2 and CDH2-associated genes were predicted using the Encyclopedia of RNA Interactomes (ENCORI) database. The expression of genes in clinical THCA tissues was investigated from the Human Protein Atlas (HPA) database and validated by qRT-PCR. We conducted the cell functions pathways of CDH2 and CDH2-associated gene FRMD3 by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. We also showed the correlation between CDH2 and FRMD3 expression and tumor immune infiltration. Results: The expression of CDH2 was significantly higher in THCA tumor tissues compared to normal tissues. Moreover, there were strongly associations of CDH2 expression with the stages T and N. Cellular function assays showed that CDH2 exerted its growth-promoting activity of THCA. To better understand how CDH2 was regulated in THCA, we sought genes associated with CDH2. Correlation analysis revealed that there were negative correlations between genes (CDH2, FRMD3) and miRNAs (hsa-miR-410-3p, hsa-miR-411-5p, hsa-miR-299-5p). Moreover, CDH2 and FRMD3 expression were significantly higher in tumor tissues than in normal tissues, while hsa-miR-410-3p, hsa-miR-411-5p and hsa-miR-299-5p were significantly decreased in tumor tissues compared with normal tissues in THCA. GO and KEEG results showed that CDH2 and FRMD3 were strongly associated with immune-related functions. High expression of CDH2 and FRMD3 was linked to the suppression of immune cells. There were strong negativity correlations between CDH2, FRMD3 and T-cell exhaustion factors. Conclusion: Our data indicated that CDH2 and CDH2-related gene FRMD3 might have the critical effects on altering tumors becoming 'cold tumors' eventually leading to immune checkpoint inhibitor resistance.

Knockdown of lncRNA PCAT6 suppresses the growth of non-small cell lung cancer cells by inhibiting macrophages M2 polarization via miR-326/KLF1 axis.

Non-small cell lung cancer (NSCLC) is the most common malignant tumor of lung, which seriously threatens the life of people. It has been reported that lncRNA prostate cancer-associated transcript 6 (PCAT6) could facilitate the metastasis of NSCLC cells. However, whether lncRNA PCAT6 in NSCLC cells could affect the tumor microenvironment (TME) remains unclear. In the present study, the level of PCAT6 in NSCLC cells was detected using RT-qPCR. The effects of PCAT6 knockdown on the viability and apoptosis in NSCLC cells were detected with CCK-8 and flow cytometry assay. NSCLC cell-derived exosomes were isolated with ultracentrifugation. Next, transwell assay was conducted to assess the migration and invasion of NSCLC cells. Dual-luciferase reporter assay was performed to verify the relationship among PCAT6, miR-326, and KLF1 in A549 cells. In addition, nanoparticle tracking analysis (NTA) was applied to detect the particle size of isolated exosomes. Moreover, ELISA assay was performed to detect the levels of IL-1ß and IL-10 in the supernatant of macrophage. We found knockdown of PCAT6 significantly inhibited the viability, migration, and invasion of NSCLC cells. In addition, dual-luciferase reporter assay illustrated that miR-326 was the target of PCAT6 and KLF1 was the target of miR-326 in NSCLC cells. Moreover, NSCLC cells-derived exosomes could promote macrophages M2 polarization by transporting PCAT6. Meanwhile, macrophages M2 polarization was able to promote the metastasis and epithelial-mesenchymal transition (EMT) process of NSCLC cells via regulating PCAT6/miR-326/KLF1 axis. Taken together, knockdown of lncRNA PCAT6 suppressed the growth of NSCLC cells by inhibiting macrophages M2 polarization via miR-326/KLF1 axis.

Continuous intravenous infusion of recombinant human endostatin using infusion pump plus chemotherapy in non-small cell lung cancer.

BACKGROUND: Lung cancer is one of the deadliest cancers in the world with the highest incidence and mortality rate among all cancers. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of primary lung cancer. However, efficacy and safety of the current regimens for NSCLC is unsatisfactory. Therefore, there has been an increasing urgency for development of potential therapeutic therapies for NSCLC. AIM: To investigate the therapeutic outcomes and safety of continuous intravenous infusion of recombinant human endostatin (Rh-endostain) using an infusion pump in retreated advanced NSCLC. METHODS: Patients with retreated advanced NSCLC who were admitted to Zhejiang Provincial People's Hospital from October 2017 to April 2019 were recruited. These patients received continuous intravenous infusion of Rh-endostain using an infusion pump. Objective response rate (ORR), clinical benefit rate (CBR), median progression-free survival (mPFS), and incidences of adverse events (AEs) were analyzed after treatment. RESULTS: A total of 45 patients with retreated advanced NSCLC were included, and all of them were evaluated. In these patients, ORR was 22.2%, CBR was 84.4%, and mPFS was 5.3 mo. The following AEs were observed, decreased hemoglobin (34 cases, 75.6%), nausea/vomiting (32 cases, 71.1%), elevated transaminase (24 cases, 53.3%), leukopenia (16 cases, 35.6%), thrombocytopenia (14 cases, 31.1%), and constipation (1 case, 3.4%). None of the patients had leukopenia, nausea /vomiting, and constipation of grade III and above. CONCLUSION: The patients showed improved adherence to 5-d continuous intravenous infusion of Rh-endostain using an infusion pump. Favorable efficacy and safety of this treatment regimen were achieved in retreated advanced NSCLC.

Demethoxycurcumin increases the sensitivity of cisplatin-resistant non-small lung cancer cells to cisplatin and induces apoptosis by activating the caspase signaling pathway.

Patients with non-small cell lung cancer (NSCLC) can develop strong drug resistance following long-term treatment with platinum-based drugs. Increasing doses of chemotherapeutic drugs fail to obtain better results, and serious complications occur. It has been demonstrated that upregulation of excision repair cross-complementary 1 (ERCC1) in lung cancer cells is closely associated with cell resistance to platinum-based chemotherapy. In addition, curcumin (CMN) enhances antitumor effects in NSCLC by downregulating ERCC1. The aim of the present study was to investigate the effects of demethoxycurcumin (DMC), a curcuminoid, on the reversal of resistance of NSCLC cells in vitro and in vivo. The present study demonstrated that DMC significantly increased the sensitivity of DDP in DDP-resistant A549 (A549/DDP) cells. The results from an MTT assay demonstrated that DMC combined with DDP significantly attenuated the proliferation of A549/DDP cells. Furthermore, DMC exhibited decreased toxicity in normal lung fibroblast MRC-5 cells. In addition, following treatment of A549/DDP cells with a combination of DMC and DDP, the expression of ERCC1 was reduced, the protein levels of Bcl-2 and Bax were decreased and increased, respectively, whereas caspase-3 was activated, according to results from western blotting. Finally, DDP combined with DMC significantly attenuated A549/DDP cell-derived tumor growth in vivo. Taken together, the findings from the present study suggested that DMC in combination with DDP may be considered as a novel combination regimen for restoring DDP sensitivity in DDP-resistant NSCLC cells.

CYFRA 21-1 is an early predictor of chemotherapeutic effectiveness in advanced nonsmall cell lung cancer: An observational study.

Serum cytokeratin 19 fragment (CYFRA21-1) has been found to be a useful prognostic marker in lung cancer. Previous studies have revealed that change in CYFRA21-1 synchronously predicted therapeutic effectiveness in advanced nonsmall cell lung cancer (NSCLC) after the second cycle of chemotherapy. The objective of this study was to investigate the early predictive value of percentage change in serum CYFRA21-1 from pretreatment to completion of the first cycle of chemotherapy for chemotherapeutic effectiveness in advanced NSCLC patients.Ninety-seven advanced NSCLC patients with elevated serum CYFRA21-1 level (≥3.8 µg/L), who received 2 platinum-containing drugs, were included in this retrospective study. Serum CYFRA21-1 had been assayed before and after the first cycle of chemotherapy. To evaluate the effectiveness of chemotherapy, patients were allocated to disease control (DC) and progressive disease groups. The percentage changes of serum CYFRA21-1 concentration before and after first-cycle chemotherapy that occurred in each group were evaluated for their ability to predict achievement of radiologic DC, that is, to predict therapeutic effectiveness.The percentage change of serum CYFRA21-1 and the prevalence of ≥5% weight loss were higher in patients with progressive disease than in those with DC. The differences in other clinical and pathological variables including age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, cigarette smoking, histological type, gross type, clinical stage, and chemotherapy regimens of the 2 groups were not significant. Both multiple generalized linear model analysis and linear trend tests indicated that the percentage change of serum CYFRA21-1 concentration was independently and negatively linked to the effectiveness of chemotherapy for NSCLC (P < 0.01). The area under the receiver-operating characteristic curve of the percentage change in prediction of DC was 0.84 and the optimal cut-off value was17.5% (P < 0.001).The percentage change of serum CYFRA21-1 after completing the first cycle of chemotherapy was predictive of treatment effects and might be helpful in making early decisions to change chemotherapy regimens in patients with advanced NSCLC.