Expression of Wip1 in serum of patients with small cell lung cancer and its clinical significance / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the expression of wild type p53 induced phosphatase 1 (Wip1) in small cell lung cancer (SCLC) cells and the serum of SCLC patient and its relationship with clinical prognosis. Methods: Real time quantitative PCR (qPCR) was used to detect the expression of Wip1 in SCLC cells and serum samples. Results: The expression of Wip1 in drug-resistant SCLC cells was significantly higher than that in sensitive cell lines (P<0.01). The expression of Wip1 in serum of SCLC group was significantly higher than that of normal control group (P<0.05); the expression of Wip1 in serum of patients with chemotherapy resistance was significantly higher than that in patients with chemotherapy sensitivity (all P<0.05); the serum Wip1 level was correlated with disease stage, chemotherapy sensitivity and survival status of SCLC patients (all P<0.05). The area under ROC curve of Wip1 predicting the prognosis of SCLC was 0.836 (95%CI:0.8230-0.9600, P<0.01); the expression lever of Wip1 was significantly correlated with progression free survival and overall survival time of SCLC patients (all P<0.05). Disease stage, chemosensitivity and Wip1 expression were independent prognostic factors for SCLC patients (all P<0.05). Conclusion: The expression of Wip1 in serum of SCLC patients may be related to chemotherapy sensitivity and prognosis. Wip1 may be a potential biomarker for therapeutic efficacy and prognosis evaluation of SCLC patients.

miR-9 regulates the malignant biological behaviors of small cell lung cancer by targeting zinc finger E-box binding homeobox 2 and its possible mechanism / 中国肿瘤生物治疗杂志

@#[Abstract] Objective：To explore the regulatory effect of miR-9 on biological behaviors of small cell lung cancer (SCLC) cells by targeting zinc finger E-box binding homeobox 2 (ZEB2), and to analyze the role of miR-9 in SCLC and its possible mechanism. Methods: qPCR, WB and immunohistochemistry methods were used to detect the mRNA and protein expressions of ZEB2 in cancer tissues and corresponding adjacent tissues of 67 SCLC patients who received surgical treatment at the Department of Oncology, Fourth Hospital of Hebei Medical University from February 2018 to November 2019. TargetScan was used to predict the potential target gene of miR-9, which was later verified by Dual luciferase reporter gene assay, qPCR and WB methods. CCK-8 method, Flow cytometry and Transwell experiment were used to detect the effect of miR-9 and ZEB2 over-expression on the biological behaviors of NCI-H446 cells, and WB was used to detect the protein expressions of E-cadherin, N-cadherin and Vimentin in cells. NCI-H446 cells overexpressing miR-9 were used to construct SCLC nude mouse xenograft model, and the effect of miR-9 on the growth of xenografts was observed. Results: The mRNA and protein expression levels of ZEB2 in SCLC tissues were significantly higher than those in adjacent tissues (P<0.01). There is a potential binding site on the 3' UTR of ZEB2 to bind with miR-9. Compared with the control group, the mRNA and protein expression levels of ZEB2 in NCI-H446 cells of the miR-9 over-expression group were significantly reduced (P<0.01); the proliferation, migration and invasion abilities of NCI-H446 cells were significantly suppressed (P<0.05 or P<0.01), and the expression of EMT protein was reduced; However, simultaneous over-expression of ZEB2 could reverse above effects. In in vivo experiments, the size and weight of transplanted tumors in the miR-9 over-expression group were significantly lower than those in the control group (P<0.05 or P<0.01). The expression of ZEB2 protein in the tumor tissues of nude mice in the miR-9 overexpression group was significantly lower than that in the control group (P<0.01). Conclusion: miR-9 can inhibit the biological behaviors of SCLC cells and the growth of NCI-H446 transplanted tumors in nude mice by targeting and regulating ZEB2.

Change of peripheral blood sPD-L1 during chemotherapy in patients with small cell lung cancer and its clinical significance / 中国肿瘤临床

Objective: In tumor microenvironment, immune-related mechanisms up-regulate the expression of programmed death li-gand 1 (PD-L1), which abnormally activates PD-L1 signaling pathway and mediates tumor immune escape. Soluble programmed death ligand 1 (sPD-L1) is a form of PD-L1. It has been confirmed that the expression of sPD-L1 in lung squamous cell carcinoma and adeno-carcinoma is related to disease progression, while small cell lung cancer (SCLC) has a high degree of malignancy, strong invasiveness and few related studies. The purpose of this study was to observe the changes in expression of sPD-L1 in the plasma of SCLC patients and their clinical significance. Methods: A total of 94 patients with SCLC diagnosed by pathological examination in Shanxi Provincial Cancer Hospital from March 2018 to November 2018 were selected as test group, and 17 healthy persons in the same period were se-lected as control group. The dynamic changes of plasma sPD-L1 were compared between the two groups, and the correlations among the expression of sPD-L1 and TNM stage, distant metastasis, and pro-gastrin-releasing peptide (ProGRP) was analyzed. Results: The lev-el of sPD-L1 in the test group was higher than that in the control group (P<0.05 and P<0.01, respectively). In patients with SCLC in the remission stage, the serum sPD-L1 level after chemotherapy was significantly lower than that before chemotherapy (P<0.01); in pa-tients with advanced stage, the serum sPD-L1 level after chemotherapy was significantly higher than that before chemotherapy (P<0.01). The abnormal high expression of sPD-L1 in SCLC patients was significantly correlated with the progression of the disease (P<0.05). The expression of sPD-L1 in serum was positively correlated with the tumor marker ProGRP. Conclusions: The expression of sPD-L1 in peripheral plasma of patients with SCLC is higher than that in healthy individuals and is closely related to the clinical effect.

Comparison of the efficacy and safety of cisplatin, etoposide, and irinotecan combined with chemotherapy and topotecan monotherapy as second-line treatment for patients with sensitive relapsed SCLC / 中国肿瘤临床

Objective: To investigate whether combination chemotherapy with cisplatin, etoposide, and irinotecan was better than topotecan alone as second-line chemotherapy in patients with sensitive relapsed small cell lung cancer (SCLC). Method: Between September, 2014 and September, 2017, the patients'data were collected in Jilin Province Cancer Hospital. All patients were diagnosed with sensitive relapsed SCLC. Thirty-six patients received combination chemotherapy containing cisplatin plus etoposide plus irinotecan, and 42 patients received topotecan alone. Combination chemotherapy consisted of five 2-week courses of intravenous cisplatin 25 mg/m2 on days 1 and 8, intravenous etoposide 60 mg/m2 on days 1-3, and intravenous irinotecan 90 mg/m2 on day 8. Topotecan therapy consisted of at least one course of intravenous topotecan 1.5 mg/m2 on days 1-5, every 3 weeks. The primary endpoints were progression-free survival (PFS) and overall survival (OS), and safety was assessed in all patients who received at least one dose of drugs. Results: PFS was significantly longer in the combination chemotherapy group [median 5.3 months, 95% confidence interval (CI) 4.3-5.8] than in the topotecan group (3.2 months, 95% CI: 2.7-4.0;P=0.0030); OS was also significantly increased in the combination chemotherapy group (median 16.3 months, 95% CI: 13.8-19.1) than in the topotecan group (13.1 months, 95% CI: 10.2-15.4; P=0.0097). The most common grade 3/4 adverse events were neutropenia [31 (86.1%) patients in the combination chemotherapy group vs. 28 (66.7%) patients in the topotecan group], anemia [26 (72.2%) vs. 10 (23.8%)], leucopenia [29 (80.6%) vs . 21 (50.0%)], and thrombocytopenia [13 (36.1%) vs . 11 (26.2%)]. One treatment-related death (febrile neutropenia with pulmonary infection) occurred in the combination chemotherapy group, and none occurred in the topotecan group. Conclusions:Combination chemotherapy with cisplatin plus etoposide plus irinotecan could be considered a treatment option in second-line che-motherapy for selected patients with sensitive relapsed SCLC. However, the combination chemotherapy group had a higher incidence of adverse events than the topotecan group, and appropriate drug dosages should be explored.

SPIDR significantly suppressed in tissues of small cell lung cancer promotes NCI-H446 cells proliferation by reducing serum dependence / 中国肿瘤生物治疗杂志

@# Objective: The present study was aimed to explore the role and distinctive mechanism of SPIDR, the key regulatory protein of homologous recombination pathway, in progression of small cell lung cancer (SCLC). Methods: 60 SCLC specimens and 44 normal lung tissues were collected from the patients undergoing tumor resection and bronchoscopic puncture in Shanghai Pulmonary Hospital Affiliated to Tongji University from January 2013 to January 2015. The expression of SPIDR in clinical samples and NCIH446 (SCLC cell line) and MRC-5 (normal cell line) were assayed by Real-time PCR. The role of SPIDR in SCLC was investigated in vivo and in vitro by the expression of SPIDR were artificially modified in NCI-H446. Results: Smoking was significantly associated with the occurrence of SCLC (P<0.01). The expression of SPIDR mRNAin SCLC tissues was lower than that of normal lung tissues (P <0.01), and the SPIDR transcriptional and translational levels of NCI-H446 cells were also lower than that of MRC-5.Although there is no significant changes of cell growth rate and susceptibility to cisplatin and etoposide in the NCI-H446 cells overexpressing SPIDR. However, the volume of xenograft tumors of overexpressed SPIDR group decreased by 58.99% (P<0.01) and 61.84% (P<0.01) than that of the original NCI-H446 cells and the NCI-H446 cells transfected with vector (pMSCV) and the average tumor mass decreased by 61.70% (P<0.01) and 70.25% (P<0.01) respectively. When the fetal bovine serum content in the medium was reduced to 3%, the growth rate of NCI-H446 cells overexpressing SPIDR was 22.33% (P<0.01) and 20.24% (P<0.05) lower than that of the original NCIH446 cells and control group, the similar results were obtained from the 1% serum concentration experiment as well. Conclusion: The expression of SPIDR, the key regulatory protein in the DNAdouble strand break homologous recombination repair pathway, was significantly suppressed in SCLC tissues, which markedly accelerated the growth of NCI-H446 cells in vivo and reduced the reliance of NCIH446 cells to the serum. The detailed mechanism is worthy of further investigation.

The clinical research about early diagnosis of small cell lung cancer through mad2 de-tection / 中国肿瘤临床

Objective:To explore combined detection of mad2 with anti-nuclear mitotic spindle apparatus antibody(MSA)and anti-centromere antibody(ACA)and their clinical value for the diagnosis of small cell lung cancer(SCLC).Methods:One hundred and twen-ty SCLC patients,110 non-small cell lung cancer(NSCLC)patients,and 115 pulmonary nodule(PN)patients were enrolled in this study. The expression of mad2 was analyzed by qt-PCR.MSA and ACA were detected by indirect immunofluorescence(IIF)staining.Results:mad2 was overexpressed in SCLC and NSCLC samples(P<0.05).There were significant differences between the results obtained for SCLC and NSCLC samples by qt-PCR(P<0.05).AUC in ROC curve for mad2 expression was 0.799 with an intermediate diagnostic value. In the correlative analysis,the odds ratio of MSA and ACA was 6.94 and 5.60,respectively.In the correlation analysis,Kappa value of mad2 with MSA was 0.49,and Kappa value of mad2 with ACA was 0.42.In the parallel analysis,the sensitivity and specificity was 83.31% and 79.34%,respectively,while the Youden Index was 0.62.Moreover,in the serial analysis,the sensitivity and specificity was 65.32% and 93.35%,respectively,and the Youden Index was 0.59.Conclusions:In comparison with the NSCLC and PN samples,mad2 was overexpressed in SCLC samples.Therefore,mad2 ought to play a critical role in the pathology of SCLC.The combined expression of mad2 with MSA and ACA may contribute to enhancing the sensitivity and specificity of detection;this expression may allow early diag-nosis and clinical diagnosis of SLCC and may be a promising treatment for SCLC.

Inductive effect of temozolomide on small cell lung cancer H446 cell apoptosis / 中国生化药物杂志

Objective To explore the effect of temozolomide on apoptosis and molecular mechanism in small cell lung cancer (SCLC) cell H446. Methods The effect of temozolomide on the viability of H446 cell was measured by MTT assay.The effect of temozolomide on cell cycle was detected by flow cytometry.The activation of phosphatidyl inositol 3-kinase (PI3K)/AKT signaling pathway and expression level of downstream target genes (Cyclin B1), cell division cycle 2 (Cdc2), Bax, Bcl-2 and Survivin were detected by western blot.Results Temozolomide (50, 100, 200 μmol/L) could inhibit H446 cell viability, and the inhibitory rate was highest at 48 h.Moreover, temozolomide made H446 cell cycle arrested in G2 phase.Western blott showed the expression of PI3K, Cyclin B1, Cdc2, Bcl-2, Survivin and the phosphorylation of AKT were reduced, but the expression of Bax were increased by temozolomide.Conclusion Temozolomide could induce SCLC cell H446 apoptosis via blocking PI3K/AKT signal pathway.

Syndrome of Inappropriate Antidiuretic Hormone Secretion in Small Cell Lung Cancer / 中国肿瘤临床

Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) was a common complica-tion of small cell lung cancer (SCLC). Recent studies have suggested that the origin of this disease is related to seceration of tumor cells and application of medecine. The inappropriate antidiuretic hormone secretion can lead to disturbance of metabolism of water and sodium, resulting in hyponatremia. Because the symp-toms are atypical, the diagnosis is difficult. Many cases are misdiagnosed or misseddiagnosed. The primary tumor must be treated and the restriction of water intake is the main and effective method to deal with SIADH. Prognosis of SCLC patients with SIADH is poor in most reports.

Prognostic Significance of Supraclavicular Lymph Nodes and Pleural Effusion In Small Cell Lung Cancer / 결핵

BACKGROUNDS: In the absence of distant metastasis, small cell lung cancer (SCLC) patients presenting with supraclavicular lymph node (SCLN) involvement and pleural effusion can benefit from thoracic radiotherapy. But there are some debate as to the prognostic significance of both SCLN involvement and pleural effusion. The purpose of this study was to determine the prognostic significance of SCLN involvement and pleural effusion in SCLC. METHODS: Two Hundred and fifteen patients with histologically confirmed small cell lung cancer, who were treated either at the Keimyung university Dongsan hospital and Kyungpook national university hospital from January 1994 to June 1998, were evaluated retrospectively. The patients were classified as having either limited or extensive stage using the Veterans Administration staging system. RESULTS: SCLN was presented in 10.5% of patients(n=21). The median survival was 247 days for patients with SCLN(n=21) and 264 days for patients without(n=194) (p=0.52). After treatment, the median survival was 298 days for patients with SCLN(n=13) and 348 days for patients without(n=115) (p=0.52). SCLN involvement was not correlated with the presence of distant metastases. Medican survival was 459 days for patients with a limited stage without SCLN(n=66), 650 days for those with a limited stage with SCLN (n=7) (p=0.96). Pleural effusion was presented in 24.7% of patients(n=52). The median survival was 198 days for patients with pleural effusion(n=52) and 275 days for patients without(n=163) (p<0.05). After treatment, the median survival was 294 days for patients with a pleural effusion(n=25) and 286 days for patients without(n=103) (p=0.39). The presence of pleural effusion was not correlated with that of distant metastases. The median survival was 395 days for patients with a limited stage without a pleural effusion(n=63), 451 days for those with a limited stage with pleural effusion(n=10) (p=0.92). CONCLUSIONS: In this study, SCLN involvement does not explain the poor survival rate and the relevance to extensive staged disease. Furthermore, the existence of a pleural effusion did not correlated with the presence of distant metastases. However, the presence of a pleural effusion appears to be a minor prognostic factor in our study. Therefore supraclavicular lymph node justify any amendment to the staging system currently used.

Immunohistochemical Staining of Insulin-like Growth Factor-1 in Human Lung Cancer cells of NSCLC and SCLC / 결핵

OBJECTIVE: Lung cancer arises after a series of morphological changes, which take several years to progress from normal epithelium to invasive cancer. Multiple molecular changes and growth factors factor production have been documented in lung cancers, both small cell and non-small cell types. Insulin-like growth factors(IGFs) are important mitogenic and anabolic peptides, both in vivo and in vitro, and are thought to be significant autocrine-paracrine factors involved in normal and malignant cell proliferation. In this study, we have investigated (delete) the degree of expression of IGF-1 on the immunohistochemical staining in human non-small cell lung cancer(NSCLC) cells and small cell lung cancer (SCLC) cells were investigated. METHODS: Immunohistochemical staining for IGF-1 was performed in 15 cases of small cell carcinoma, 15 cases of squamous cell carcinoma, 15 cases of adenocarcinoma, and 12 cases of bronchoalveolar carcinoma. RESULTS: The NSCLC cells showed significantly increased expression The expression of IGF-1 on the immunohistochemical staining significantly increased in NSCLC cells than in SCLC cells. CONCLUSION: These results suggest that IGF-1 are expressed the expression of IGF-1 in human lung cancer cells(.), and the (The) immunohistochemical staining of IGF-1 in lung cancer cell lines may help in differentiation of may assist in the differentiation of NSCLC and SCLC.

A study on regulation of DNA mismatch repair genes MLH1 and MSH2 in human SCLC cell line H446 under hypoxic condition / 中国癌症杂志

Background and purpose:Regulation of MMR activity under hypoxia may play an important role in genetic instability of cancer,but the mechanism is still unclear.We investigated the expression of DNA mismatch repair genes MLH1 and MSH2 in human SCLC cell line H446 under hypoxic condition and explore the role of promoter methylation of genes in hypoxia.Methods:RT-PCR and Western blot were applied to detect MLH1 and MSH2 expression in human SCLC cell line H446 at the mRNA and the protein level,respectively,under either hypoxic condition or after 5-Aza-CdR treatment.Meanwhile,methylation-specific PCR(MSP)was used to determine promoter methylation of MLH1 and MSH2.Results:The expression of MLH1 and MSH2 in H446 cells significantly decreased both at the mRNA and the protein level under hypoxic condition.5-Aza-CdR treatment led to the restoration of MLH1 and MSH2 expression,while,both MLH1 and MSH2 were down-regulated again after removing 5-Aza-CdR.Conclusions:The promoter methylation of MLH1 and MSH2 may play an important role in its defective expression in H446 cells under hypoxic condition.And 5-Aza-CdR could restore MLH1 and MSH2 expression.

A Case of Cushing's Syndrome Associated with Ectopic Corticotropin Production in Patient with Small-Cell Lung Cancer / 결핵

Small cell lung cancer(SCLC) is frequently associated with paraneoplastic syndromes, which occur in approximately 20% of patients at presentation. Clinical Cushing's syndrome secondary to ectopic ACTH production is uncommon, occurring in approximately 5% of all SCLC patients. However, biochemical evidence of hypercortisolism can be detected in up to 50% of patients. Patients with Cushing's syndrome from ectopic ACTH production show hypertension, weakness, hyperglycemia, and hypokalemic metabolic alkalosis, but differ from patients with classic Cushing's disease in that symptoms develop more rapidly. Ectopic ACTH production is associated with a poor response to chemotherapy, short survival, and a high risk of treatment-related complications. We report a case of Cushing's syndrome associated with ectopic corticotropin production in 59-year-old male patient with extensive stage of SCLC.

Clinical Diagnostic Value of CT Scan and Serum Tumor Markers Determination for SCLC / 实用放射学杂志

Objective To investigate the clinic diagnosis value of CT scan and the determination of serum NSE, Cyfra21-1 for SCLC. Methods ① The CT findings and pathologic basis of 220 cases with SCLC were analyzed retrospectively.② Between February 2000 and December 2001, 120 consecutive patients with pulmonary lesions by CT scan, which suspiciously suffered lung cancer, were studied prospectively. Serum samples were obtained by venous puncture from all patients 1 week prior to surgery or puncture biopsy. The serum concentration of NSE, Cyfra21-1 were determinated using ELISA. According to the pathologic result, the diagnostic value of CT scan, NSE and Cyfra21-1 were evaluated.Results ① Most CT findings of SCLC were central and spindly or eggplant-shape mass, hilar and/or mediastinal lymph nodes enlargement.The obstructive pulmonary lesions were found rarely.② Using CT scan, NSE and Cyfra21-1 alone, the sensitivity were 75%,72.5% and 32.5%,the specificity were 73.75%, 83.75% and 48.75%,the accuracy were 74.16%, 81.67% and 43.33% respectively. With combination of CT scan and NSE, the diagnostic accuracy was 78.3%, and the sensitivity was 87.5%. However, CT scan combined with Cyfra21-1 can not be improve the diagnostic value. Conclusion SCLC has specific CT findings. The sensitivity of CT scan was 75%, combinated with NSE, its accuracy was higher(78.3%), and the sensitivity was 87.5%.