CDK4/6 Inhibitors Impede Chemoresistance and Inhibit Tumor Growth of Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is characterized by rapid development of chemoresistance and poor outcomes. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) are widely used in breast cancer and other cancer types. However, the molecular mechanisms of CDK4/6 in SCLC chemoresistance remain poorly understood. Here, Rb1flox/flox, Trp53flox/flox, Ptenflox/flox (RTP) and Rb1flox/flox, Trp53flox/flox, MycLSL/LSL (RPM) spontaneous SCLC mouse models, SCLC cell line-derived xenograft (CDX) models, and SCLC patient-derived xenograft (PDX) models are established to reveal the potential effects of CDK4/6is on SCLC chemoresistance. In this study, it is found that CDK4/6is palbociclib (PD) or ribociclib (LEE) combined with chemotherapeutic drugs significantly inhibit SCLC tumor growth. Mechanistically, CDK4/6is do not function through the classic Retionblastoma1 (RB) dependent axis in SCLC. CDK4/6is induce impair autophagy through the AMBRA1-lysosome signaling pathway. The upregulated AMBRA1 protein expression leads to CDK6 degradation via autophagy,  and the following TFEB and TFE3 nuclear translocation inhibition leading to the lysosome-related genes levels downregulation. Moreover, it is found that the expression of CDK6 is higher in SCLC tumors than in normal tissue and it is associated with the survival and prognosis of SCLC patients. Finally, these findings demonstrate that combining CDK4/6is with chemotherapy treatment may serve as a potential therapeutic option for SCLC patients.

Enhanced degradation of 2,4-dichlorophenol in groundwater by defective iron-based metal-organic frameworks: Role of SO3- and electron transfer.

The purposeful formation of crystal defects was regarded as an attractive strategy to enhance the catalytic activity of Fe-MOFs. In this study, the pyrolytic hydrochloric acid-modulated MIL-101-NH2 (P250HMN-2) was fabricated for the first time, and the important role of pyrolysis in the formation of crystal defects was confirmed. PDS was introduced as an enhancer for the P250HMN-2/Na2SO3 system. Without pH adjustment, 99.7 % of 2,4-DCP was removed by the P250HMN-2/Na2SO3/PDS system in 180 min. The catalytic performance of P250HMN-2 improved 2.5-fold than that of MIL-101-NH2. It was found that the high density of Fe-CUSs on P250HMN-2 were the major active sites, which could efficiently react with SO32- to generate ROS through electron transfer. The results of quenching experiments, probe tests, and EPR tests indicated that SO3-, SO4-, 1O2, OH, and SO5- were involved in the 2,4-DCP degradation process, with SO3-, SO4-, and 1O2 playing major roles. Moreover, P250HMN-2 could effectively degrade 2,4-DCP for 148 h in a fixed-bed reactor with excellent stability and reusability, indicating a promising catalyst for practical applications.

Anemia status of infants and young children aged six to thirty-six months in Ma'anshan City: A retrospective study.

BACKGROUND: Anemia in infants and young children can have long-term effects on cognitive and physical development. In Ma'anshan City, China, there has been growing concern about the prevalence of anemia among children aged 6 to 36 mo. Understanding the factors influencing this condition is crucial for targeted interventions and improving overall child health in the region. AIM: To analyze the anemia status and influencing factors of infants and young children aged 6 to 36 mo in Ma'anshan City, China. Providing scientific evidence for reducing the incidence of anemia and improving the health level of children in this age group. METHODS: The study encompassed 37698 infants and young children, aged from 6 to 36 mo, who underwent health examinations at the Ma'anshan Maternal and Child Health Hospital from January 2018 to October 2022 were included in the study. Basic information, physical examination, and hemoglobin detection data were collected. Descriptive analysis was used to analyze the prevalence of anemia in children in the region, and univariate analysis was used to analyze the influencing factors of anemia. RESULTS: The mean hemoglobin level of infants and young children aged 9 to 36 mo increased with age, and the anemia detection rate decreased with age. The anemia detection rate in rural infants aged 6, 9, and 12 mo was higher than that in urban infants. Although the anemia detection rate was higher in 6-mo-old boys than girls, it was higher in 24-mo-old girls than boys. There were statistically significant differences in the anemia detection rates among 9-mo-old and 12-mo-old infants with different nutritional statuses (emaciation, overweight, obese, and normal). Moreover, there were no statistically significant differences in anemia detection rates among infants and young children with different nutritional statuses at other ages. Besides, the anemia detection rates in obese infants aged 9 and 12 mo were higher than those in normal and overweight infants, with statistically significant differences. Finally, there were no statistically significant differences in the anemia detection rates between emaciation infants and those with other nutritional statuses. CONCLUSION: The anemia situation among infants and young children aged 6 to 36 mo in Ma'anshan City, China, is relatively prominent and influenced by various factors. Our result shown that attention should be paid to the anemic infant and young child population, with strengthened education and targeted prevention and dietary guidance to help them establish good living habits, improve nutritional status, and reduce the occurrence of anemia to improve children's health levels.

Hydrothermal Synthesis of a Technical Lignin-Based Nanotube for the Efficient and Selective Removal of Cr(VI) from Aqueous Solution.

Aminated lignin (AL) was obtained by modifying technical lignin (TL) with the Mannich reaction, and aminated lignin-based titanate nanotubes (AL-TiNTs) were successfully prepared based on the AL by a facile hydrothermal synthesis method. The characterization of AL-TiNTs showed that a Ti-O bond was introduced into the AL, and the layered and nanotubular structure was formed in the fabrication of the nanotubes. Results showed that the specific surface area increased significantly from 5.9 m2/g (TL) to 188.51 m2/g (AL-TiNTs), indicating the successful modification of TL. The AL-TiNTs quickly adsorbed 86.22% of Cr(VI) in 10 min, with 99.80% removal efficiency after equilibration. Under visible light, AL-TiNTs adsorbed and reduced Cr(VI) in one step, the Cr(III) production rate was 29.76%, and the amount of total chromium (Cr) removal by AL-TiNTs was 90.0 mg/g. AL-TiNTs showed excellent adsorption capacities of Zn2+ (63.78 mg/g), Cd2+ (59.20 mg/g), and Cu2+ (66.35 mg/g). After four cycles, the adsorption capacity of AL-TiNTs still exceeded 40 mg/g. AL-TiNTs showed a high Cr(VI) removal efficiency of 95.86% in simulated wastewater, suggesting a promising practical application in heavy metal removal from wastewater.

METTL3 promotes chemoresistance in small cell lung cancer by inducing mitophagy.

BACKGROUND: Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer. Although most patients are initially sensitive to first-line combination chemotherapy with cisplatin and etoposide, chemotherapy drug resistance easily develops and quickly leads to tumour progression. Therefore, understanding the mechanisms of chemotherapy drug resistance and how to reverse it is key to improving the prognosis of patients with SCLC. Moreover, N6-methyladenosine (m6A) is the most abundant mRNA modification and is catalysed by the methyltransferase complex, in which methyltransferase-like 3 (METTL3) is the sole catalytic subunit. METHODS: The effects of METTL3 on chemoresistance in SCLC cells were determined using qRT-PCR, Western blotting, immunohistochemistry, cell counting kit (CCK-8) assays, flow cytometry, and tumorigenicity experiments. Methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP qPCR, immunofluorescence, and drug inhibitor experiments were performed to confirm the molecular mechanism of Decapping Protein 2 (DCP2), which is involved in the chemoresistance of SCLC. RESULTS: In the present study, we found that METTL3 is a marker for poor SCLC prognosis, and it is highly expressed in chemoresistant SCLC cells. METTL3 promotes SCLC chemoresistance by positively regulating mitophagy. METTL3 induces m6A methylation of DCP2 and causes the degradation of DCP2, which promotes mitochondrial autophagy through the Pink1-Parkin pathway, leading to chemotherapy resistance. We also found that STM2457, a novel METTL3 inhibitor, can reverse SCLC chemoresistance. CONCLUSIONS: The m6A methyltransferase METTL3 regulates Pink1-Parkin pathway-mediated mitophagy and mitochondrial damage in SCLC cells by targeting DCP2, thereby promoting chemotherapy resistance in patients with SCLC.

Prognostic value of circulating tumor DNA using target next-generation sequencing in extensive-stage small-cell lung cancer.

BACKGROUND: Chemotherapy remains the mainstay of treatment for small-cell lung cancer (SCLC). Liquid biopsies provide a convenient and non-invasive detection method for monitoring disease progression in patients with SCLC. METHODS: We performed next-generation sequencing of 159 plasma samples from 69 patients with extensive-stage (ES)-SCLC. Circulating tumor (ct)DNA levels were quantified in haploid genome equivalents per mL (hGE/mL). MuTect2 was used to detect single nucleotide variants and short insertions/deletions. The "enrichKEGG" function in the "clusterProfiler" R package was used to enrich the mutated genes that only appeared during disease progression. RESULTS: In our cohort, 66 of 69 (95.7%) plasma samples at the time of diagnosis had detectable somatic mutations; TP53 (89%) and RB1(56%) were the most frequent mutations, as well as copy number variations in some common SCLC-related genes such as RB1. Combination ctDNA and tissue testing improved the overall detection rate of actionable mutations from 19.4% to 26.9% compared with that of tissue detection alone. In addition, ctDNA levels changed dynamically during the course of treatment and were significantly associated with decreased progression-free survival. Notably, actionable mutations were detected at the time of diagnosis and during disease progression. CONCLUSIONS: Our study revealed a dynamic somatic mutation profile through continuous ctDNA detection and confirmed that ctDNA levels can reflect tumor burden and predict PFS in patients with extensive stage-SCLC. Furthermore, we demonstrated that plasma ctDNA assays can provide real-time information on somatic mutations for potential targeted therapies for SCLC.

Identifying CDC7 as a synergistic target of chemotherapy in resistant small-cell lung cancer via CRISPR/Cas9 screening.

There is currently a lack of efficacious treatments for patients with chemo-resistant small-cell lung cancer (SCLC), leading to poor prognoses. We examined a chemo-resistant SCLC cell line using genome-wide CRISPR/Cas9 screening and identified serine/threonine kinase cell division cycle 7 (CDC7) as a potential synergistic target. Silencing CDC7 in chemo-resistant SCLC cells decreased the IC50 and improved the efficacy of chemotherapy. Based on the highest single agent model, the CDC7 inhibitor XL413 had a synergistic effect with both cisplatin and etoposide in chemo-resistant SCLC cells, but had no such effect in chemo-sensitive SCLC cells; the combination of XL413 and chemotherapy significantly inhibited cell growth. Western blot and flow cytometry showed that the combined treatments increased apoptosis, whereas XL413 alone had little effect on apoptosis. An analysis of cell cycle and cyclin protein levels indicated that the combination of XL413 and chemotherapy-induced G1/S phase arrest and DNA damage in chemo-resistant SCLC cells. Xenografted tumor and histoculture drug response assays using patient-derived xenografts showed that XL413 improved the efficacy of chemotherapy in vivo and with SCLC tissues. These results suggest that XL413 exerts a synergistic effect with chemotherapy on chemo-resistant SCLC.

Ligand-independent EphA2 contributes to chemoresistance in small-cell lung cancer by enhancing PRMT1-mediated SOX2 methylation.

Chemoresistance is the crux of clinical treatment failure of small-cell lung cancer (SCLC). Cancer stem cells play a critical role in therapeutic resistance of malignant tumors. Studies have shown that the role of erythropoietin-producing hepatocellular A2 (EphA2) in tumors is complex. This study aimed to test the hypothesis that ligand-independent activation of EphA2 modulates chemoresistance by enhancing stemness in SCLC. We verified that EphA2 was activated in chemoresistance sublines in a ligand-independent manner rather than a ligand-dependent manner. Ligand-independent EphA2 enhanced the expression of stemness-associated biomarkers (CD44, Myc, and SOX2), accelerated epithelial-mesenchymal transition (EMT) and reinforced self-renewal to drive the chemoresistance of SCLC, while the P817H mutant EphA2 neutralized intrinsic function. Co-immunoprecipitation (co-IP) and GST-pull down experiments were conducted to verify that EphA2 directly interacted with PRMT1. Moreover, EphA2 increased the expression and activity of PRMT1. Whereafter, PRMT1 interacted with and methylated SOX2 to induce stemness and chemoresistance in SCLC. Pharmacological inhibition of EphA2 showed a synergistic anti-tumor effect with chemotherapy in preclinical models, including patient-derived xenograft (PDX) models. These findings highlight, for the first time, that the EphA2/PRMT1/SOX2 pathway induces chemoresistance in SCLC by promoting stemness. EphA2 is a potential therapeutic target in SCLC treatment.

Study on ionic association behavior in sodium nitrate solution.

Raman spectroscopy combined with component analysis and molecular dynamics simulation were used to study chemical species and their transformation in aqueous sodium solutions. Study shows that the characteristic vibrational frequency of nitrate ions (ν1-NO3-) blue-shifted from 1043.9 to 1046.9 cm-1, and the full width at half maximum increased from 6.8 to 10.8 cm-1 as the concentration increasing. When water/salt molar ratio (WSR) > 30, the relative concentration (RC) of free hydrated ions and solvent shared ion pair accounts for the vast majority, and there is almost no contact ion pair in solution. When WSR less than 30, due to the continuous reduction of the number of water molecules, the hydrated water molecules around the sodium ions and nitrate ions begin to decrease, and solvent shared ion pair or contact ion pair gradually forms. Sodium ions and nitrate ions mainly exist in a monodentate coordination. When WSR > 160, both the relative concentration of contact ion pair and complex structure is close to 0. This work proves that a lower RC of complex structure in solution, a smaller supersaturation of the solution is achieved, meaning aqueous sodium nitrate solution is easier to nucleate crystals.

Cell plasticity in patients with NSCLC: The controversial origins of transformed SCLC.

In recent years, the application of targeted therapy has greatly improved the survival of NSCLC patients with known tumor mutations. However, the plasticity of tumor cells can drive them to transform into a phenotypic state that is no longer targeted by drugs. One of the mechanisms by which drug resistance occurs is the transformation from NSCLC to SCLC. This seems to occur because of the selection pressure exerted by the drugs. However, the transformation has also been observed in non-targeted patients, which challenges the origin of transformed SCLC. In the present study, the current clinical understanding of transformed SCLC is summarized along with the current understanding of its genome status and cloning history in cancer progression. This was done to explore the origins of transformed SCLC, find key molecular markers to predict the occurrence of the transformation, and permit timely adjustment of patients' treatment plans. Besides, the current clinical trials on transformed SCLC are discussed. Finally, recommendations are made on the problems that need to be solved to improve the diagnosis and treatment of patients with transformed SCLC.

NRBF2 regulates the chemoresistance of small cell lung cancer by interacting with the P62 protein in the autophagy process.

Reversing chemotherapy resistance in small cell lung cancer (SCLC) is crucial to improve patient prognosis. The present study aims to investigate the underlying mechanisms in SCLC chemoresistance. We see that nuclear receptor binding factor 2 (NRBF2) is a poor prognostic factor in SCLC. The effects of NRBF2 on chemoresistance were determined in SCLC. The underlying molecular mechanisms of NRBF2 in the autophagy process in SCLC were examined. NRBF2 positively regulated autophagy, leading to drug resistance in SCLC. The MIT domain of NRBF2 directly interacted with the PB1 domain of P62. This interaction increased autophagic P62 body formation, revealing the regulatory role of NRBF2 in autophagy. Notably, NRBF2 was directly modulated by the transcription factor XRCC6. The MIT domain of NRBF2 interacts with the PB1 domain of P62 to regulate the autophagy process, resulting in SCLC chemoresistance. NRBF2 is likely a useful chemotherapy response marker and therapeutic target in SCLC.

Intermittent Theta Burst Stimulation vs. High-Frequency Repetitive Transcranial Magnetic Stimulation in the Treatment of Methamphetamine Patients.

Background and Aims: In this brief report, we compare the effectiveness and safety of intermittent theta burst stimulation (iTBS) and conventional 10 Hz repetitive transcranial magnetic stimulation (rTMS) in patients with methamphetamine use disorder (MAUD). Our study suggests that iTBS would also reduce drug craving in patients with MAUD just as the 10 Hz; thus, there may be no difference in treatment effects between these two methods. Methods: In total twenty male methamphetamine (MA) addicts were randomly assigned to iTBS (n = 10) or 10 Hz (n = 10) groups for 12 treatments. Cue-evoked cravings, anxiety, depression, and withdrawal symptoms were measured at baseline before the first treatment, and post-tests after days 10, 15, and 20. Results: The results showed that iTBS and 10 Hz treatment had similar effectiveness in reducing cue-induced craving in male addicts for MA. Both 10 Hz and iTBS improved withdrawal symptoms of patients with MAUD. Conclusions: Intermittent theta burst stimulation may be similar in effectiveness as 10 Hz in treating patients with MAUD. The clinical usefulness of rTMS could be improved substantially because of the increase in its capacity, cost, and accessibility. Importantly, the effectiveness of rTMS in the treatment of patients with MAUD is not yet proven, and should be tested in the large double-blind sham-controlled studies.

MHC-II Signature Correlates With Anti-Tumor Immunity and Predicts anti-PD-L1 Response of Bladder Cancer.

A large proportion of anti-tumor immunity research is focused on major histocompatibility complex class I (MHC-I) molecules and CD8+ T cells. Despite mounting evidence has shown that CD4+ T cells play a major role in anti-tumor immunity, the role of the MHC-II molecules in tumor immunotherapy has not been thoroughly researched and reported. In this study, we defined a MHC-II signature for the first time by calculating the enrichment score of MHC-II protein binding pathway with a single sample gene set enrichment analysis (ssGSEA) algorithm. To evaluate and validate the predictive value of the MHC class II (MHC-II) signature, we collected the transcriptome, mutation data and matched clinical data of bladder cancer patients from IMvigor210, The Cancer Genome Atlas (TCGA) databases and Gene Expression Omnibus (GEO) databases. Comprehensive analyses of immunome, transcriptome, metabolome, genome and drugome were performed in order to determine the association of MHC-II signature and tumor immunotherapy. We identified that MHC-II signature is an independent and favorable predictor of immune response and the prognosis of bladder cancer treated with immune checkpoint inhibitors (ICIs), one that may be superior to tumor mutation burden. MHC-II signature was significantly associated with increased immune cell infiltration and levels of immune-related gene expression signatures. Additionally, transcriptomic analysis showed immune activation in the high-MHC-II signature subgroup, whereas it showed fatty acid metabolism and glucuronidation in the low-MHC-II signature subgroup. Moreover, exploration of corresponding genomic profiles highlighted the significance of tumor protein p53 (TP53) and fibroblast growth factor receptor 3 (FGFR3) alterations. Our results also allowed for the identification of candidate compounds for combined immunotherapy treatment that may be beneficial for patients with bladder cancer and a high MHC-II signature. In conclusion, this study provides a new perspective on MHC-II signature, as an independent and favorable predictor of immune response and prognosis of bladder cancer treated with ICIs.

WITHDRAWN: lncRNA Linc00173 modulates glucose metabolism and multidrug chemoresistance in SCLC: Potential molecular panel for targeted therapy.

This article has been withdrawn at the request of the editor-in-chief. Following publication of this article, the editor-in-chief discovered evidence of image duplication in Figures 1I, 1J, 3F, S5B, and S6B. Given the duplication of several western blots representing several gene products, the editor-in-chief has lost faith in the findings presented in this article. The authors maintain that these image duplications were the result of errors in file management and do not affect the conclusions of the study. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

High mutations in fatty acid metabolism contribute to a better prognosis of small-cell lung cancer patients treated with chemotherapy.

BACKGROUND: The majority of patients with small-cell lung cancer (SCLC) show a good response in the early stages of treatment, but more than 90% of patients will develop drug resistance. Therefore, biomarkers are urgently needed to identify patients who can benefit from systemic treatment. METHODS: We prospectively enrolled 52 extensive-stage SCLC patients before treatment from a local hospital to identify mutations related to patient prognosis, and verified them in the published Jiang's cohort and George's cohort. RESULTS: We found that patients with high mutations (mut-high) in the fatty acid (FA) metabolism pathway had a longer progression-free survival (PFS) in the local hospital cohort (HR = 0.446, 95% CI, 0.207-0.959, p = 0.0387) and a longer overall survival (OS) in Jiang's cohort (HR = 0.549, 95% CI, 0.314-0.960, p = 0.0351) than patients with low mutations (mut-low). Multivariate analysis suggested that mut-high status was an independent prognostic factor in both cohorts. George's cohort verified that mut-high status was associated with a longer OS than mut-low status (HR = 0.730, 95% CI 0.440-1.220, p = 0.2277). The possible mechanisms were as follows: the frequency of mutated FA synthase (FASN) in the mut-high group was greater than that in the mut-low group, and pathways related to the cell cycle, DNA repair, and oxidative phosphorylation were enriched in the mut-high group. CONCLUSIONS: The prognosis of SCLC patients treated with chemotherapy was better among patients with more mutations in the FA metabolism pathway, and the underlying mechanisms could be found at the genome and transcriptome levels.

Inhibition of lncRNA KCNQ1OT1 Improves Apoptosis and Chemotherapy Drug Response in Small Cell Lung Cancer by TGF-ß1 Mediated Epithelial-to-Mesenchymal Transition.

PURPOSE: Drug resistance is one of the main causes of chemotherapy failure in patients with small cell lung cancer (SCLC), and extensive biological studies into chemotherapy drug resistance are required. MATERIALS AND METHODS: In this study, we performed lncRNA microarray, in vitro functional assays, in vivo models and cDNA microarray to evaluate the impact of lncRNA in SCLC chemoresistance. RESULTS: The results showed that KCNQ1OT1 expression was upregulated in SCLC tissues and was a poor prognostic factor for patients with SCLC. Knockdown of KCNQ1OT1 inhibited cell proliferation, migration, chemoresistance and promoted apoptosis of SCLC cells. Mechanistic investigation showed that KCNQ1OT1 can activate transforming growth factor-ß1 mediated epithelial-to-mesenchymal transition in SCLC cells. CONCLUSION: Taken together, our study revealed the role of KCNQ1OT1 in the progression and chemoresistance of SCLC, and suggested KCNQ1OT1 as a potential diagnostic and prognostic biomarker in SCLC clinical management.

ESRP1 regulates alternative splicing of CARM1 to sensitize small cell lung cancer cells to chemotherapy by inhibiting TGF-ß/Smad signaling.

Epithelial splicing regulatory protein 1 (ESRP1) is an RNA-binding protein that regulates alternative splicing of mRNA. ESRP1 plays an important role in chemoresistance of various cancers, including breast cancer, colon cancer and non-small cell lung cancer. However, the role of ESRP1 and its mechanism in small cell lung cancer (SCLC) chemoresistance remains unclear. In this study, we found that ESRP1 is significantly downregulated in SCLC chemo-resistant cells compared with chemo-sensitive cells. Moreover, the expression of ESRP1 was significantly lower in SCLC tissues than that in normal adjacent tissues and positively correlated with overall survival. Overexpression of ESRP1 increased SCLC chemosensitivity, and induced cell apoptosis and cell cycle arrest, whereas knockdown of ESRP1 induced the opposite effects. ESRP1 could inhibit the growth of SCLC in vivo. Through mRNA transcriptome sequencing, we found that ESRP1 regulates coactivator-associated arginine methyltransferase 1 (CARM1) to produce two different transcripts CARM1FL and CARM1ΔE15 by alternative splicing. ESRP1 affects the chemoresistance of SCLC by changing the content of different transcripts of CARM1. Furthermore, CARM1 regulates arginine methylation of Smad7, activates the TGF-ß/Smad pathway and induces epithelial-to-mesenchymal transition (EMT), thereby promoting SCLC chemoresistance. Collectively, our study firstly demonstrates that ESRP1 inhibits the TGF-ß/Smad signaling pathway by regulating alternative splicing of CARM1, thereby reversing chemoresistance of SCLC. The splicing factor ESRP1 may serve as a new drug resistance marker molecule and a potential therapeutic target in SCLC patients.

Linc00173 promotes chemoresistance and progression of small cell lung cancer by sponging miR-218 to regulate Etk expression.

The functional effects of long noncoding RNAs (lncRNAs) in cancer have been widely recognized. However, there is little research on SCLC-related lncRNAs. Here, long intergenic nonprotein coding RNA 173 (Linc00173) was first shown to be involved in chemoresistance and progression of small-cell lung cancer (SCLC). We found that Linc00173 was highly expressed in SCLC chemoresistant cell lines, and promoted SCLC cells chemoresistance, proliferation, and migration-invasion. Animal studies validated that Linc00173 induced tumor chemoresistance and growth of SCLC in vivo. Moreover, Linc00173 upregulated Etk through functioning as a competitive endogenous RNA (ceRNA) by "sponging" miRNA-218 and led to the upregulation of GSKIP and NDRG1, resulting in the translocation of ß-catenin. Importantly, expression analysis revealed that both Linc00173 and Etk were upregulated in SCLC patient samples and exhibiting positive Linc00173/Etk correlation. High expression of Linc00173 closely correlated with chemoresistance, extensive stage, and shorter survival in SCLC patients. Collectively, our study illustrated a Linc00173-mediated process that facilitated chemoresistance and progression in SCLC, which might provide treatment strategy against SCLC.

A novel mutation panel for predicting etoposide resistance in small-cell lung cancer.

PURPOSE: Platinum-based chemotherapy, consisting of etoposide and cisplatin (EP), has been the cornerstone of therapy for extensive-stage small-cell lung cancer (ES-SCLC) for decades. Despite the marked initial sensitivity of SCLC to chemotherapy, EP regimens cannot avoid the emergence of drug resistance in clinical practice. With the rise of new chemotherapy regimens in recent years and the primary resistance or insensitivity of ES-SCLC to EP regimens, it is desirable to be able to identify patients with resistant or insensitive ES-SCLC. METHODS: The sequencing and drug sensitivity data of SCLC cell lines were provided by The Genomics of Drug Sensitivity in Cancer Project (GDSC). The data regarding sensitivity to etoposide of 54 SCLC cell lines were analyzed, and etoposide-sensitive cell lines and etoposide-resistant cell lines were differentiated according to the IC50 values defined by the GDSC. ROC curve analysis was performed on all mutations and combinations of mutations to select the optimal panel to predict resistance to etoposide. RESULTS: ROC analysis of etoposide resistance revealed that the most significant single gene mutation indicating resistance to etoposide was CSMD3, and the accuracy of predicting resistance to etoposide proved to be the highest when there was any mutation in CSMD3/PCLO/RYR1/EPB41L3, area under the curve =0.804 (95% confidence interval: 0.679-0.930,P <0.001). CONCLUSION: This study found that a panel with four genes (CSMD3, EPB41L3, PCLO, and RYR1) can accurately predict sensitivity to etoposide. These findings provide new insights into the overall treatment for patients with ES-SCLC that is resistant or insensitive to etoposide.