Non-small-cell lung cancer (NSCLC) is the leading cause of cancer deaths in the world and often diagnosed at an advanced stage, so it is urgent to explore the pathogenesis and new diagnostic biomarkers. Accumulated evidences suggested that small nucleolar RNAs (snoRNAs) played a key role in the development and progression of NSCLC. To examine differential expression snoRNA profile and identify snoRNAs with clinical significance in lung adenocarcinoma (LUAD), The Cancer Genome Atlas (TCGA) LUAD RNA sequencing dataset was used to investigate differential expression snoRNA signatures and compared with snoRNA PCR array analysis in pair-matched LUAD tissues. The diagnostic ability of SONRD60 was assessed using a receiver operating characteristic (ROC) curve. The Kaplan-Meier method was used to plot survival curves. Univariate and multivariate Cox regression analyses were used to investigate the prognostic effect of SNORD60 expression on LUAD. The results showed that SNORD60 was a significantly upregulated snoRNA after intersection analysis in LUAD cases. SNORD60 has 74.2% sensitivity and 75.3% specificity for the diagnosis of LUAD. Increased SNORD60 expression was linked with lymph node metastases and the TNM stage ( P < 0.05 ). Pathological T category and lymph node metastases were independent prognostic factors for overall survival in a multivariate Cox regression study. Our findings demonstrated that SNORD60, a small nucleolar RNA, has an oncogenic function in LUAD and might be used as a new early diagnostic biomarker for LUAD.

Nonsmall cell lung cancer (NSCLC) is a major type of lung cancer. In current study, we aim to evaluate whether the combination of Ku70/80 heterodimer protein inhibitor STL127705 and gemcitabine would be more favorable approach for the treatment of NSCLC compared with monotreatment with gemcitabine. Clongenic survival assay was used to determine the survival and sensitivity to irradiation. H1299 was stained with fluorescein isothiocyanate-Annexin V, and cell apoptosis was measured by flow cytometry. H1299 cells were transfected with nonhomologous end-joining (NHEJ) repair reporter, and stable cell line was selected by puromycin. NHEJ activity was determined based on the intensity of green fluorescent protein. DNA double-strand breaks (DSBs) were determined by the fluorescence intensity of γH2AX using flow cytometry. The mRNA expressions of Ku70 and Ku80 were determined using quantitative real-time PCR. Combination of STL127705 enhanced sensitivity of NSCLC cell lines to irradiation when compared with treatment with gemcitabine alone. However, small cell lung cancer cell line was not affected. H1299 cells treated with STL127705 in combination with gemcitabine showed a significantly increased apoptosis compared with H1299 cells treated with gemcitabine alone. Moreover, STL127705 treatment dramatically reduced NHEJ activity in H1299 cells when compared with gemcitabine single treatment. Increased DSBs were consistently observed in H1299 when treated with the combination of STL127705 and gemcitabine. However, the mRNA levels of Ku70 and Ku80 were upregulated by the combination treatment. It demonstrated that STL127705 enhanced antitumor activity of gemcitabine. Mechanistically, treatment with STL127705 enhanced DNA damage via inhibiting NHEJ pathway, blocking DNA-PK, and forming Ku70/80 heterodimer, eventually leading to tumor cells apoptosis.

e20517 Background: Metastasis tumor is the leading cause of lung cancer-related deaths, including local metastasis and distant metastasis. Despite its crucial clinical significance, local metastasis of lung cancer is still largely uncharacterized in terms of underlying molecular mechanisms. Here, we performed TSO500 (Illumina, San Diego, CA, USA) sequencing with 19 matched lung cancer primary and local metastatic samples to comprehensively profiling of lung cancer molecular characteristics. Methods: 19 lung cancer patients with paired primary tumor and local metastatic samples were enrolled, including 16 matched primary-lymph node samples and 3 primary-pleura samples. We compared molecular characteristics, including SNV and TMB, of matched samples. Molecular alterations identified were classified into shared (mutations in both primary and metastases) and private (mutations only in primary or metastases) groups. Thus, share mutation statistical analysis, pathway level enrichment and mutational signature was also done. Results: Comprehensively analysis of matched samples showed that mutational concordance between primary tumor and local metastases is lower. The average rate of concordance of primary-lymph node and primary-pleura was 40.6%±28.4%, 39.0%±33.9% respectively. Obviously, no difference in TMB between local metastases and primary tumor was found, average of primary vs lymph node and primary vs pleura was 7.5 vs 6.5, 6.9 vs 4.2 respectively. Significantly, we found that smoking lung cancer patients have higher TMB compared to non-smokers(p < 0.01), regardless primary tumor or metastatic lymph nodes. Conclusions: Lung cancer has higher inter-tumor heterogeneity with proportion of shared mutations less than 50%. Meanwhile, smoking lung cancer has higher TMB in both primary tumor and metastatic lymph nodes compared to non-smokers.