Real-world evidence of osimertinib in Chinese patients with EGFR T790M-positive non-small cell lung cancer: a subgroup analysis from ASTRIS study.

PURPOSE: ASTRIS study aimed the largest to evaluate the effectiveness and safety of second- or higher-line osimertinib in patients with advanced/metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) in the real-world setting. Here we report the results of Chinese patients in ASTRIS study. METHODS: Adults with EGFR T790M-positive advanced NSCLC pretreated with EGFR-tyrosine kinase inhibitor (EGFR-TKI), having a WHO performance status score of 0-2 and asymptomatic, stable central nervous system (CNS) metastases were included. All patients received once-daily osimertinib 80 mg orally. The outcomes included investigator-assessed clinical response, progression-free survival (PFS), time-to-treatment discontinuation (TTD), and safety. RESULTS: A total of 1350 patients were included. Response rate was 55.7% (95% confidence interval [CI] 0.53-0.58). The median PFS and the median TTD were 11.7 months (95% CI 11.1-12.5) and 13.9 months (95% CI 13.1-15.2), respectively. Overall, 389 patients (28.8%) had at least one protocol-specified adverse event (AE); AEs of interstitial lung diseases/pneumonitis-like events and QT prolongation were reported in 3 (0.2%) and 59 (4.4%) patients, respectively. CONCLUSION: Osimertinib was effective in Chinese patients with T790M-positive NSCLC who had progressed after first- or second-generation EGFR-TKI in real-word setting and the results were consistent with ASTRIS study overall population and AURA studies. No new safety signals or events were identified. CLINICAL TRIAL NUMBER: NCT02474355.

Elevated Serum and Hair Levels of Cadmium as a Risk Factor for Liver Carcinoma: A Meta-Analysis.

BACKGROUND: Cadmium (Cd) exposure might confer cancer risk. Published studies on the association between Cd levels and liver cancer risk have generated conflicting results. We aimed to conduct a meta-analysis to address the controversy. METHODS: Relevant literature was searched from the popular bio-databases up to Nov 2022. Essential information was extracted and data were pooled to assess the association between Cd levels and liver cancer risk. Subgroup analysis on sample types and geographical locations was conducted. Then, sensitivity analysis and bias diagnosis were performed to test the credibility of the results. RESULTS: Eleven publications comprising 14 independent studies were selected for analysis and the overall pooled data showed that Cd levels were markedly higher in liver cancer patients than those in healthy controls (SMD = 2.00; 95% CI = 1.20-2.81; P < 0.05). To get a prices estimation, the subgroup analyses showed that Cd levels in serum (SMD = 2.55; 95% CI = 1.65-3.45; P < 0.05) and hair (SMD = 2.08; 95% CI = 0.34-3.81; P < 0.05) were significantly higher in liver cancer patients than those in the healthy controls, respectively. CONCLUSIONS: In summary, the data showed that Cd levels were markedly higher in liver cancer patients than those in healthy controls, indicating that Cd accumulation might play important role in the neoplastic transformation of liver cells.

Abscopal effect triggered by radiation sequential mono-immunotherapy resulted in a complete remission of PMMR sigmoid colon cancer.

Background: Radiation therapy combined with immune checkpoint inhibitors (ICIs) has recently turned into an appealing and promising approach to enhance the anti-tumor immunity and efficacy of immunological drugs in many tumors. Abscopal effect induced by radiation is a phenomenon that often leads to an efficient immunity response. In this study, we investigated whether the combination of the immunogenic effects derived from radiotherapy sequential ICIs-based therapy could increase the incidence of abscopal effects, and improve the survival rates. Case presentation: We described a clinical case regarding a 35-year-old male patient who was admitted to our hospital with a diagnosis of adenocarcinoma of the sigmoid colon and synchronous multiple liver metastases following a surgical resection. The molecular pathological examination showed immune-desert phenotype and proficient mismatch repair (pMMR). The patient was treated with adjuvant chemotherapy after surgery, however, after 7 months, multiple metastasis in the pelvic lymph nodes were diagnosed. Unfortunately, the tumor progressed despite multiple cycles of chemotherapy combined with cetuximab or bevacizumab. Within the follow-up treatment, the patient was administered with only 50Gy/25F of radiation dose to treat the anastomotic lesions. Subsequently, mono-sindilizumab was used as systemic therapy, leading to a rapid reduction of all pelvic lesions and complete clinical remission. So far, the patient survived for more than 20 months under continuous mono-sindilizumab treatment and is still in complete remission. Conclusion: A localized radiotherapy combined with a sindilizumab-based systemic therapy may overcome the immune resistance of pMMR metastatic colorectal cancer (mCRC), thus obtaining greater efficacy of the therapy. Its mechanism may be related to the abscopal effect obtained by the synergistic use of radiation and sindilizumab, which should be further investigated in the future.

Fibronectin 1 as a Key Gene in the Genesis and Progression of Cadmium-Related Bladder Cancer.

Exposure to cadmium (Cd), a non-essential heavy metal, leads to the malignant transformation of urothelial cells and promotes bladder cancer (BC) development, but the mechanisms are unclear. Therefore, we aimed to explore the possible molecules associated with Cd-related BC. By analyzing and mining biological big data in public databases, we screened genes associated with the malignant transformation of uroepithelial cells caused by Cd and further screened the key gene associated with BC prognosis from these genes. The possible roles of the key gene in BC progression were then further explored through biological big data analysis and cellular experiments. Data mining yielded a total of 387 malignant transformation-related genes, which were enriched in multiple cancer-related signaling pathways, such as cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway, and Jak-STAT signaling pathway. Further screening identified Fibronectin 1 (FN1) as the key gene. High expression of FN1 was associated with the advanced pathologic stage, T stage, N stage, and M stage and predicted an unfavorable outcome in BC patients. FN1 expression was positively associated with the infiltration of several types of immune cells, particularly tumor-associated macrophages and cancer-associated fibroblasts. Overexpression of FN1 could be detected in Cd-treated urothelial cells and BC cell lines. Interestingly, silencing of FN1 impaired the proliferation and invasive capacity of BC cells. In conclusion, the present study provides new insight into the mechanism of Cd-related BC. FN1 might be a prognostic marker and therapeutic target for BC. Future studies are needed to confirm these results.

The histone deacetylase SIRT6 promotes glycolysis through the HIF-1α/HK2 signaling axis and induces erlotinib resistance in non-small cell lung cancer.

Erlotinib is a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Overcoming erlotinib resistance is crucial to improve the survival of advanced non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations. It is also an important clinical problem that urgently needs a solution. In this study, we explored strategies to overcome erlotinib resistance from the perspective of energy metabolism. SIRT6 is a histone deacetylase. Here, we found that high expression of SIRT6 is associated with poor prognosis of lung adenocarcinoma, especially in EGFR-mutated NSCLC patients. The next cell experiment found that SIRT6 expression increased in erlotinib-resistant cells, and SIRT6 expression was negatively correlated with the sensitivity of NSCLC to erlotinib. Inhibition of SIRT6 promoted erlotinib-induced apoptosis in erlotinib-resistant cells, and glycolysis in drug-resistant cells was also inhibited. Functional studies have shown that SIRT6 increases glycolysis through the HIF-1α/HK2 signaling axis in drug-resistant cells and inhibits the sensitivity of NSCLC cells to erlotinib. In addition, the HIF-1α blocker PX478-2HCL attenuated the glycolysis and erlotinib resistance induced by SIRT6. More importantly, we confirmed the antitumor effect of SIRT6 inhibition combined with erlotinib in NSCLC-bearing mice. Our findings indicate that the cancer metabolic pathway regulated by SIRT6 may be a new target for attenuating NSCLC erlotinib resistance and has potential as a biomarker or therapeutic target to improve outcomes in NSCLC patients.

Efficacy and safety of recombinant human endostatin during peri-radiotherapy period in advanced non-small-cell lung cancer.

Background: This study aimed to retrospectively investigate the efficacy and safety of recombinant human endostatin (Rh-endostatin) combined with radiotherapy in advanced non-small-cell lung cancer (NSCLC). Methods: Patients with unresectable stage III and IV NSCLC who treated with radiotherapy were enrolled. Patients who received Rh-endostatin infusion throughout the whole peri-radiotherapy period formed the Endostar group, and those who received no Rh-endostatin infusion were the control group. Results: The median progression-free survival was 8.0 and 4.4 months (hazard ratio: 0.53; 95% CI: 0.32-0.90; p = 0.019) and median overall survival was 40.0 and 13.1 months (hazard ratio: 0.53; 95% CI: 0.28-0.98; p = 0.045) for the Endostar and control groups, respectively. The Endostar group exhibited a numerically lower rate of radiation pneumonitis relapse, radiation pneumonitis death and pulmonary fibrosis. Conclusion: Rh-endostatin infusion throughout the peri-radiotherapy period enhanced radiosensitivity and showed better survival outcomes and a tendency toward fewer radiation-related pulmonary events in patients with NSCLC.

Recombinant human endostatin (Rh-endostatin/Endostar) combined with chemotherapy has been approved as first-line standard treatment in patients with advanced non-small-cell lung cancer (NSCLC) in China. This study aimed to retrospectively investigate the efficacy and safety of Rh-endostatin combined with radiotherapy in advanced NSCLC. Patients with unresectable stage III and IV NSCLC who treated with radiotherapy were enrolled. Patients who received Rh-endostatin infusion throughout the whole peri-radiotherapy period were the Endostar group, and those receiving no Rh-endostatin infusion were the control group. Results showed that the median progression-free survival was 8.0 and 4.4 months, and median overall survival was 40.0 and 13.1 months, for the Endostar and control groups, respectively. The Endostar group had a lower rate of radiation pneumonitis relapse, radiation pneumonitis death and pulmonary fibrosis. In conclusion, Rh-endostatin infusion throughout the peri-radiotherapy period enhanced radiosensitivity and showed better survival outcomes and a tendency toward fewer radiation-related pulmonary events in patients with NSCLC.

Malignant transformation of ovarian teratoma responded well to immunotherapy after failed chemotherapy: a case report.

Mature cystic teratomas (MCTs), also known as dermoid cysts, are the most common ovarian germ cell tumors and the most common ovarian neoplasms in patients younger than 20 years. MCTs mainly appear as pelvic masses that are made up of different types of well differentiated derivates of at least two germinative cell types. MCT of the ovary is always benign lesions with slow growth and good prognosis. Unfortunately, in about 1-2% of cases, it may undergo malignant transformation. At present, surgical treatment is the preferred option for the early stage of malignant transformation of teratomas, while with a high postoperative recurrence rate. For advanced or recurrent malignant ovarian teratomas, the effect of conventional chemotherapy or radiotherapy is poor, leading to high mortality. Thus, identifying novel treatment for malignant transformed MCTs is an urgently need in clinic. Recently, PD-1 antibody-based immunotherapy has achieved great success in treatment of lung cancer, melanoma, and other malignant tumors. However, its effect on the malignant transformation of ovarian teratomas has not yet been reported. Here we reported a patient who suffered malignant transformation of ovarian teratoma and responded well to camrelizumab, an anti-PD-1 inhibitor.

The Efficacy and Safety of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Combined With Thymosin in Advanced Non-Small Cell Lung Cancer Patients Harboring Active Epidermal Growth Factor Receptor Mutations.

OBJECTIVE: To explore the efficacy and safety of EGFR-TKI combined with thymosin therapy in advanced non-small cell lung cancer (NSCLC) patients harboring active EGFR mutations. METHODS: Patients confirmed as advanced NSCLC with active EGFR mutations were recruited from August 2008 to July 2018 retrospectively. Patients treated with EGFR-TKI were classified as the EGFR-TKI group. And those received EGFR-TKI and thymosin therapy were designated as the EGFR-TKI plus thymosin group. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), tumor response and adverse effects. RESULTS: The median PFS was significantly longer in EGFR-TKI plus thymosin group than that in EGFR-TKI group (14.4 months vs. 9.2 months; HR=0.433, 95% CI 0.322 - 0.582, P<0.0001). The median OS was also prolonged in EGFR-TKI plus thymosin group than that in EGFR-TKI group (29.5 months vs. 19.8 months; HR=0.430, 95% CI 0.319 - 0.580, P<0.0001). The objective response rate in EGFR-TKI plus thymosin group and EGFR-TKI group were 60.0% versus 60.8% (P=0.918). The disease control rate was 96.9% in EGFR-TKI plus thymosin group and 97.7% in EGFR-TKI group (P=1.000). There were no significant differences in adverse effects between the two groups. The number of CD3+T cells in peripheral blood decreased significantly after treatment including both CD3+CD4+T and CD3+CD8+T subsets in EGFR-TKI group, but not in EGFR-TKI plus thymosin group. CONCLUSIONS: Combination of EGFR-TKI and thymosin can significantly prolong the PFS and OS compared with EGFR-TKI monotherapy without more adverse events, which offers a new strategy in clinic.

Novel Biomarkers of Dynamic Blood PD-L1 Expression for Immune Checkpoint Inhibitors in Advanced Non-Small-Cell Lung Cancer Patients.

Background: Immune checkpoint inhibitors (ICIs) have become a high-profile regimen for malignancy recently. However, only a small subpopulation obtains long-term clinical benefit. How to select optimal patients by reasonable biomarkers remains a hot topic. Methods: Paired tissue samples and blood samples from 51 patients with advanced malignancies were collected for correlation analysis. Dynamic changes in blood PD-L1 (bPD-L1) expression, including PD-L1 mRNA, exosomal PD-L1 (exoPD-L1) protein and soluble PD-L1 (sPD-L1), were detected after 2 months of ICIs treatment in advanced non-small-cell lung cancer (NSCLC) patients. The best cutoff values for progression-free survival (PFS) and overall survival (OS) of all three biomarkers were calculated with R software. Results: In 51 cases of various malignancies, those with positive tissue PD-L1 (tPD-L1) had significantly higher PD-L1 mRNA than those with negative tPD-L1. In 40 advanced NSCLC patients, those with a fold change of PD-L1 mRNA ≥ 2.04 had better PFS, OS and best objective response (bOR) rate. In addition, a fold change of exoPD-L1 ≥ 1.86 was also found to be associated with better efficacy and OS in a cohort of 21 advanced NSCLC cases. The dynamic change of sPD-L1 was not associated with efficacy and OS. Furthermore, the combination of PD-L1 mRNA and exoPD-L1 could screen better patients for potential benefit from ICIs treatment. Conclusion: There was a positive correlation between bPD-L1 and tPD-L1 expression. Increased expression of PD-L1 mRNA, exoPD-L1, or both in early stage of ICIs treatment could serve as positive biomarkers of efficacy and OS in advanced NSCLC patients.

Resection and reconstruction of a giant primitive neuroectodermal tumour of the abdominal wall with an ultra-long lateral circumflex femoral artery musculocutaneous flap: a case report.

BACKGROUND: Primitive neuroectodermal tumours are clinically rare. Here, we report a case of a large peripheral primitive neuroectodermal tumour of the abdominal wall. The defect was reconstructed with the longest lateral circumflex femoral artery musculocutaneous flap reported to date. CASE PRESENTATION: A 15-year-old male suffered rupture and bleeding of an abdominal wall mass with a volume of approximately 23*18*10 cm3, involving the whole layer of the abdominal wall. Pathological examination revealed a peripheral primitive neuroectodermal tumour. The tumour was removed via oncologic resection, and the abdominal wall was reconstructed with a bilateral 44*8 cm2 lateral circumflex femoral artery musculocutaneous flap combined with a titanium polypropylene patch. The patient had smooth recovery postoperative, and the functions of the donor and recipient areas of the flap were not significantly affected. CONCLUSION: In this case report, we describe a rare primitive neuroectodermal tumour of the abdominal wall, which invaded almost the entire abdominal wall due to delay of treatment. After thoroughly removing the tumour, we immediately reconstructed the abdominal wall with an ultra-long lateral circumflex femoral artery musculocutaneous flap and achieved better appearance and function after the operation. This case suggests that we should adopt an integrated scheme of surgery combined with radiotherapy and chemotherapy in the treatment of peripheral primitive neuroectodermal tumours. Under the premise of determining the blood supply, the lateral circumflex femoral artery musculocutaneous flap can be cut to a sufficient length.

Screening of key genes and prediction of therapeutic agents in Arsenic-induced lung carcinoma.

BACKGROUND: Evidence indicates that inorganic arsenic (iAs) can directly damage cells and result in malignant transformation with unclear complicated mechanisms. In the present study, we aimed to explore the possible molecules, pathways and therapeutic agents by using bioinformatics methods. METHODS: Microarray-based data were retrieved and analyzed to screen the differentially expressed genes (DEGs) between iAs-treated lung cells and controls. Then, the functions of DEGs were annotated and the hub genes were filtrated. The key genes were selected from the hub genes through validation in The Cancer Genome Atlas (TCGA) cohorts. Possible drugs were predicted by using CMAP tool. RESULTS: Two datasets (GSE33520 and GSE36684) were retrieved, and 61 up-regulated and 228 down-regulated DEGs were screened out, which were enriched in various pathways, particularly metabolism-related pathways. Among the DEGs, four hub genes including MTIF2, ACOX1, CAV1, and MRPL17, which might affect lung cancer prognosis, were selected as the key genes. Interestingly, Quinostatin was predicted to be a potential agent reversing iAs-induced lung cell malignant transformation. CONCLUSION: The present study sheds novel insights into the mechanisms of iAs-induced lung cell malignant transformation and identified several potential small agents for iAs toxicity prevention and therapy.

Microarray-based data mining reveals key genes and potential therapeutic drugs for Cadmium-induced prostate cell malignant transformation.

Increasing evidence showed that Cadmium (Cd) can accumulate in the body and damage cells, resulting in cancerigenesis of the prostate with complex mechanisms. In the present study, we aimed to explore the possible key genes, pathways and therapeutic drugs using bioinformatics methods. Microarray-based data were retrieved and analyzed to screen differentially expressed genes (DEGs) between Cd-treated prostate cells and controls. Then, functions of the DEGs were annotated and hub genes were screened. Next, key genes were selected from the hub genes via validation in a prostate cancer cohort from The Cancer Genome Atlas (TCGA). Afterward, potential drugs were further predicted. Consequently, a gene expression profile, GSE9951, was retrieved. Then, 361 up-regulated and 30 down-regulated DEGs were screened out, which were enriched in various pathways. Among the DEGs, seven hub genes (HSPA5, HSP90AB1, RHOA, HSPD1, MAD2L1, SKP2, and CCT2) were dysregulated in prostate cancer compared to normal controls, and two of them (HSPD1 and CCT2) might influence the prostate cancer prognosis. Lastly, ionomycin was predicted to be a potential agent reversing Cd-induced prostate cell malignant transformation. In summary, the present study provided novel evidence regarding the mechanisms of Cd-induced prostate cell malignant transformation, and identified ionomycin as a potential small molecule against Cd toxicity.

Rab25 promotes erlotinib resistance by activating the ß1 integrin/AKT/ß-catenin pathway in NSCLC.

OBJECTIVES: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has significant therapeutic efficacy in non-small-cell lung cancer (NSCLC) patients. However, acquired resistance is inevitable and limits the long-term efficacy of EGFR-TKI. Our study aimed to investigate the role of ras-associated binding protein 25 (Rab25) in mediating EGFR-TKI resistance in NSCLC. MATERIALS AND METHODS: Rab25 expression in NSCLC patients was measured by immunohistochemical staining. Western blotting was used to analyse the expression of molecules in the Rab25, EGFR and Wnt signalling pathways. Lentiviral vectors were constructed to knock in and knock out Rab25. The biological function of Rab25 was demonstrated by cell-counting kit-8 and flow cytometry. The interaction between Rab25 and ß1 integrin was confirmed by co-immunoprecipitation. RESULTS: Rab25 overexpression induced erlotinib resistance, whereas Rab25 knockdown reversed this refractoriness in vitro and in vivo. Moreover, Rab25 interacts with ß1 integrin and promotes its trafficking to the cytoplasmic membrane. The membrane-ß1 integrin induced protein kinase B (AKT) phosphorylation and subsequently activated the Wnt/ß-catenin signalling pathway, promoting cell proliferation. Furthermore, high Rab25 expression was associated with poor response to EGFR-TKI treatment in NSCLC patients. CONCLUSIONS: Rab25 mediates erlotinib resistance by activating the ß1 integrin/AKT/ß-catenin signalling pathway. Rab25 may be a predictive biomarker and has potential therapeutic value in NSCLC patients with acquired resistance to EGFR-TKI.

Is Integrin Subunit Alpha 2 Expression a Prognostic Factor for Liver Carcinoma? A Validation Experiment Based on Bioinformatics Analysis.

ITGA2 (Integrin alpha-2) has been detected to be over-expressed in a number of cancers and has been suggested to be involved in cell adhesion and cell-surface mediated signaling. Our previous study using bioinformatic analyses has shown that ITGA2 might be a key gene being involved in the Cadmium-induced malignant transformation of liver cells. In the present study, we firstly aimed to learn the possible functions of ITGA2 via bioinformatics analysis, and then test its expression and clinical significance in liver carcinoma specimens through laboratory experiments. Gene ontology (GO) and pathway enrichment analysis, as well as protein-protein interaction (PPI) analysis has been conducted in Genecards. Then, a tissue microarray containing 90 cases of liver cancer and 90 paired adjacent non-cancerous samples was used for detection of ITGA2 expression by immunohistochemistry assay. Consequently, ITGA2 may be enriched in pathways regarding cell adhesion and migration. PPI analysis suggests that ITGA1, ITGB2, FLT4, LAMB1 and AGRN may have a close relationship with ITGA2. No association between ITGA2 expression and clinical parameters was observed. However, the data showed that ITGA2 might be an independent prognostic factor for liver cancer patients. In conclusion, the data suggest that ITGA2 over-expression might be a potential unfavorable prognostic factor and a potential therapeutic target for liver carcinoma.

Screening and function analysis of hub genes and pathways in hepatocellular carcinoma via bioinformatics approaches.

BACKGROUND: Liver carcinoma is a major cause of cancer-related death worldwide. Up to date, the mechanisms of liver cancerigenesis and development have not been fully understood. Multi-genes and pathways were involved in the tumorigenesis of liver cancer. OBJECTIVE: The aim of the present study was to screen key genes and pathways in liver cancerigenesis and development by using bioinformatics methods. METHODS: A dataset GSE64041 were retrieved from GEO database and the differentially expressed genes (DEGs) were screened out. Then the DEG functions were annotated by gene ontology (GO) and pathway enrichment analysis, respectively. The hub genes were further selected by protein-protein interaction (PPI) analysis. Afterwards, the mRNA and protein expressions as well as the prognostic values of the hub genes were assessed. RESULTS: As a result, 208 up-regulated and 82 down-regulated genes were screened out. These DEGs were mainly enriched in cell cycle and metabolism-related pathways. Through PPI analysis, TOP2A, PRDM10, CDK1, AURKA, BUB1, PLK1, CDKN3, NCAPG, BUB1B and CCNA2 were selected as hub genes, which were all over-expressed in liver cancers relative to those in normal tissues, respectively. Among them, PLK1 and CCNA2 were suggested to be prognostic factors for liver carcinoma. CONCLUSION: In conclusion, the present study identified several hub genes, and cell cycle and metabolism-related pathways that may play critical roles in the tumorigenesis of liver cancer. Future validation laboratory experiments are required to confirm the results.

Overexpression of SLC7A11: a novel oncogene and an indicator of unfavorable prognosis for liver carcinoma.

AIM: SLC7A11 is a gene that encodes a cystine-glutamate antiporter, which has been detected to be overexpressed in various cancers. Thus, we aimed to validate its expression and clinical significance in liver cancer. METHODS: Bioinformatic analysis was conducted and a tissue microarray was utilized for detecting SLC7A11 expression in liver cancer tissues by immunohistochemistry assay. RESULTS: High expressions of SLC7A11 have no association with clinical parameters such as age, sex and clinical stages, except for advanced pathological stages. Cox regression analysis revealed that SLC7A11 might be an independent prognostic factor for liver cancer patients. CONCLUSION: SLC7A11 overexpression might be a novel biomarker and a potential unfavorable prognostic factor as well as a potential therapeutic target for liver carcinoma.

Identification of a serum microRNA expression signature for detection of lung cancer, involving miR-23b, miR-221, miR-148b and miR-423-3p.

OBJECTIVES: Serum mircoRNAs (miRNAs), with their noticeable stability and unique expression pattern in patients with various diseases, are powerful novel non-invasive biomarkers for cancer detection. The objective of this study was to identify specific serum miRNAs as potential diagnostic markers for detection of lung cancer. MATERIALS AND METHODS: The expression of serum miRNA from treatment-naive lung cancer patients (LC), benign pulmonary disease patients (PD) and healthy controls (HC) were examined by PCR array. The study was divided into two phases: the biomarker-screening phase and the biomarker-validation phase. Logistic regression and receiver operating characteristics curve analyses were used to identify differentially expressed miRNA signatures that could distinguish LC from PD and HC. In addition, target genes of miRNAs were predicted using bioinformatic assays. RESULTS: Ten miRNAs (let-7f, miR-126-3p, miR-148b, miR-151-5p, miR-199a-3p, miR-221, miR-23b, miR-26a, miR-27b, and miR-423-3p) in LC were significantly increased compared to those in PD and HC in biomarker-validation phase (P<0.05). Bioinformatic analyses showed that predicted targets of these miRNAs might have a correlation with formation and development of cancer. Furthermore, we have developed classifiers including 4 miRNAs (miR-23b, miR-221, miR-148b and miR-423-3p) that can be demonstrated as a signature for LC detection, yielding a receiver operating characteristic curve area of 0.885. CONCLUSION: our findings define a distinct miRNA expression profile in LC cases. These 4-miRNA signatures (miR-23b, miR-221, miR-148b and miR-423-3p) may be considered as novel, non-invasive biomarker for LC diagnosis.

Identification and characterization of biomarkers and their functions for Lapatinib-resistant breast cancer.

Lapatinib, a novel oral dual tyrosine kinase inhibitor blocking HER1 and HER2 pathways, has presented beneficial effects on breast cancer with positive HER2. However, its efficacy is largely limited by the occurrence of acquired drug resistance. In this study, we aimed to explore the underlying molecular mechanisms of Lapatinib resistance using bioinformatics strategies. The gene expression profile of SKBR3-R (acquired Lapatinib-resistant) and SKBR3 (Lapatinib-sensitive) cell line was downloaded from gene expression omnibus database. Then, the differentially expressed genes (DEGs) were selected using dChip software. Furthermore, gene ontology (GO) and pathway enrichment analyses were carried out by using DAVID database. Finally, the protein-protein interaction network was constructed, and the hub genes in the network were analyzed by using STRING database. A total of 300 DEGs, such as HSPA5, MAP1LC3A and RASSF2, were screened out. GO functional enrichment analysis showed that the genes were associated with cell membrane component-related, stimulus-related and binding-related items. KEGG pathway analysis indicated that three dysfunctional pathways, including PPAR signaling pathway, cytokine-cytokine receptor interaction and pathways in cancer, were enriched. Protein-protein interaction network construction revealed that some hub genes, such as PPARG, TGFBI, TGFBR2, TIMP1, CTGF, UBA52 and JUN, might have an association with Lapatinib resistance. The present study offered new insights into the molecular mechanisms of Lapatinib resistance and identified a series of important hub genes that have the potential to be the targets for treatment of Lapatinib-resistant breast cancer.

Fisetin, a dietary phytochemical, overcomes Erlotinib-resistance of lung adenocarcinoma cells through inhibition of MAPK and AKT pathways.

Erlotinib (Tarceva) is a selective epidermal growth factor receptor tyrosine kinase inhibitor for treatment of non-small cell lung cancer (NSCLC). However, its efficacy is usually reduced by the occurrence of drug resistance. Our recent study showed that a flavonoid found in many plants, Fisetin, might have a potential to reverse the acquired Cisplatin-resistance of lung adenocarcinoma. In the present study, we aimed to test whether Fisetin could have the ability to reverse Erlotinib-resistance of lung cancer cells. Erlotinib-resistant lung adenocarcinoma cells, HCC827-ER, were cultured from the cell line HCC827, and the effects of Fisetin and Erlotinib on the cell viability and apoptosis were evaluated. The possible signaling pathways in this process were also detected. As expected, the results showed that Fisetin effectively increased sensitivity of Erlotinib-resistant lung cancer cells to Erlotinib, possibly by inhibiting aberrant activation of MAPK and AKT signaling pathways resulted from AXL suppression. In conclusion, Fisetin was a potential agent for reversing acquired Erlotinib-resistance of lung adenocarcinoma. Inactivation of AXL, MAPK and AKT pathways might play a partial role in this process.

Fisetin, a dietary bioflavonoid, reverses acquired Cisplatin-resistance of lung adenocarcinoma cells through MAPK/Survivin/Caspase pathway.

Cisplatin has been a key chemotherapy drug for treatment of non-small cell lung cancer (NSCLC) for decades. However, the efficacy of Cisplatin is usually reduced by the occurrence of drug-resistance of cancer cells. Fisetin is a flavonol naturally found in many fruits and vegetables, which has been reported to suppress cell proliferation and induce apoptosis in various cancers. In this study, we aimed to investigate whether Fisetin was capable of enhancing cytotoxicity of Cisplatin in Cisplatin-resistant NSCLC cells, and explore the possible signaling pathways involved. Cisplatin-resistant NSCLC cells, A549-CR, was established by repeated subculturing of A549 cells with increasing Cisplatin. Proliferation ability was assessed by MTT analysis and apoptosis was detected by flow cytometry. The results showed that Fisetin effectively increased sensitivity of A549-CR cells to Cisplatin, possibly mediated by inhibiting aberrant activation of MAPK signaling pathways. This increases the possibility of Fisetin as a promising agent for lung cancer therapy.