Correlation In Non-small Cell Lung Cancer Research Articles

RP11-79H23.3 Inhibits the Proliferation and Metastasis of Non-small-cell Lung Cancer Through Promoting miR-29c

Evidences indicate that long non-coding RNAs (lncRNAs) are closely involved and contributed to tumorigenesis and cancer progression. As a novel lncRNA, RP11-79H23.3 was found to be an anti-oncogene in bladder cancer. However, the essential roles and functions of RP11-79H23.3 in non-small-cell lung cancer (NSCLC) remains to be elucidated. Here, loss of functional assay was applied to gain insights into the functions of RP11-79H23.3 on the proliferation and metastasis capabilities of A549 and H1299 cells. Meantime, Real-time PCR was utilized to measure RP11-79H23.3 and miR-29c expression in NSCLC tissues. Dual-luciferase reporter assay, CCK8, colony formation assay, transwell and Western blot were performed to illustrate the potential molecular basis of RP11-79H23.3 in NSCLC. RP11-79H23.3 downregulation facilitated cell proliferation, migration, and invasion of NSCLC. The result of dual-luciferase reporter assay represented a direct interaction of RP11-79H23.3 with miR-29c, which suppressed miR-29c expression that showed inversely correlation in NSCLC. Moreover, RP11-79H23.3 siRNA facilitated the progression of NSCLC partially via regulating the expression of miR-29c and the activation of Wnt/β-catenin signaling pathway. Our findings highlighted that RP11-79H23.3, served as an anti-oncogene, accelerated NSCLC progression through sequestering miR-29c, providing a promising therapeutic target for NSCLC.

CircRACGAP1 promotes non-small cell lung cancer proliferation by regulating miR-144-5p/CDKL1 signaling pathway.

Circular RNAs (circRNAs) are involved in the regulation of many pathophysiological processes as non-coding RNAs. This study focuses on the role of circRACGAP1 in the development of non-small cell lung cancer (NSCLC). Expression patterns of circRACGAP1 and miR-144-5p in NSCLC tissues and cell lines were quantified by qRT-PCR analysis. Then, the function of circRACGAP1 on cell proliferation and tumorigenesis were confirmed in vitro and in vivo using CCK-8 assay, colony formation, EdU incorporation, and xenograft technique. The regulation of circRACGAP1 on Gefitinib resistance of NSCLC cells was evaluated by flow cytometry. The regulatory network of circRACGAP1/miR-144-5p/CDKL1 was verified by luciferase reporter assay and RNA pull-down. Western blotting analysis was performed to assess the biomarkers of cell cycle and apoptosis-associated proteins. CircRACGAP1 was highly expressed and miR-144-5p was inhibited both in NSCLC tissues and cell lines, suggesting their negative correlation in NSCLC. Knockdown of circRACGAP1 suppressed cell proliferation via arresting the cell cycle. miR-144-5p was identified as a downstream target to reverse circRACGAP1-mediated cell proliferation. miR-144-5p directly targeted the 3'-UTR of CDKL1 to regulate cell cycle of NSCLC cells. circRACGAP1 knockdown dramatically inhibited the tumor growth and enhanced the sensitivity of NSCLC to Gefitinib in vitro and in vivo. In summary, our study revealed a novel machinery of circRACGAP1/miR-144-5p/CDKL1 for the NSCLC tumorigenesis and development, providing potential diagnostic and therapeutic targets for NSCLC.

18F-FDG PET and DCE kinetic modeling and their correlations in primary NSCLC: first voxel-wise correlative analysis of human simultaneous [18F]FDG PET-MRI data

ObjectivesTo decipher the correlations between PET and DCE kinetic parameters in non-small-cell lung cancer (NSCLC), by using voxel-wise analysis of dynamic simultaneous [18F]FDG PET-MRI.Material and methodsFourteen treatment-naïve patients with biopsy-proven NSCLC prospectively underwent a 1-h dynamic [18F]FDG thoracic PET-MRI scan including DCE. The PET and DCE data were normalized to their corresponding T1-weighted MR morphological space, and tumors were masked semi-automatically. Voxel-wise parametric maps of PET and DCE kinetic parameters were computed by fitting the dynamic PET and DCE tumor data to the Sokoloff and Extended Tofts models respectively, by using in-house developed procedures. Curve-fitting errors were assessed by computing the relative root mean square error (rRMSE) of the estimated PET and DCE signals at the voxel level. For each tumor, Spearman correlation coefficients (rs) between all the pairs of PET and DCE kinetic parameters were estimated on a voxel-wise basis, along with their respective bootstrapped 95% confidence intervals (n = 1000 iterations).ResultsCurve-fitting metrics provided fit errors under 20% for almost 90% of the PET voxels (median rRMSE = 10.3, interquartile ranges IQR = 8.1; 14.3), whereas 73.3% of the DCE voxels showed fit errors under 45% (median rRMSE = 31.8%, IQR = 22.4; 46.6). The PET-PET, DCE-DCE, and PET-DCE voxel-wise correlations varied according to individual tumor behaviors. Beyond this wide variability, the PET-PET and DCE-DCE correlations were mainly high (absolute rs values > 0.7), whereas the PET-DCE correlations were mainly low to moderate (absolute rs values < 0.7). Half the tumors showed a hypometabolism with low perfused/vascularized profile, a hallmark of hypoxia, and tumor aggressiveness.ConclusionA dynamic “one-stop shop” procedure applied to NSCLC is technically feasible in clinical practice. PET and DCE kinetic parameters assessed simultaneously are not highly correlated in NSCLC, and these correlations showed a wide variability among tumors and patients. These results tend to suggest that PET and DCE kinetic parameters might provide complementary information. In the future, this might make PET-MRI a unique tool to characterize the individual tumor biological behavior in NSCLC.

Genetic profile of non-small cell lung cancer (NSCLC): A hospital-based survey in Jinhua.

BackgroundWe describe the clinical features, genetic profile, and their correlation in NSCLC patients.MethodsA total of 256 Chinese patients with NSCLC were enrolled in this study. NGS‐based genomic profiling of major lung cancer‐related genes was performed on formalin‐fixed paraffin‐embedded tumor samples.ResultsOf 256 patients with NSCLC, 219 were adenocarcinoma and most of them were in the early stage. Among patients, 63.3% patients have more than two gene mutations. By analyzing variant allele frequency (VAF), we found that the median VAF has significant differences between squamous cell carcinoma and adenocarcinoma, as well as early stage and advanced stage. The frequency of mutations in EGFR, MET, and RET were significantly higher in nonsmokers than in smokers. Besides, Pearson correlation analysis found that ALK, BRAF, and MET mutations had a strong correlation with age. Notably, higher frequencies of ALK and BRAF alterations were associated with younger age, while more frequent MET mutations appear in the patients at age 55 or older.ConclusionMore unique features of cancer driver genes in Chinese NSCLC were identified by next‐generation sequencing. These findings highlighted that it is necessary to carry out targeted detection according to different clinical features for NSCLC.

Elevated expression of G3BP1 associates with YB1 and p-AKT and predicts poor prognosis in nonsmall cell lung cancer patients after surgical resection.

PurposeG3BP1 is an RNA‐binding protein and plays roles in regulating signaling pathway. YB‐1 is a DNA/RNA binding protein encoded by YBX1 gene. Phosphorylated AKT (p‐AKT) acts as a pivotal molecule in PI3K/AKT pathway. YB‐1 drives stress granules (SGs) formation by activating G3BP1 translation under diverse conditions. SGs are involved in many different metabolic and signaling pathways which may include PI3K/AKT/mTOR. So far, there has been no report on the relationship between expression of G3BP1, p‐AKT, and YB1 and clinicopathological features/prognosis in surgically resected nonsmall cell lung cancer (NSCLC) patients.MethodsIn this study, data from TCGA (The Cancer Genome Atlas) were downloaded to investigate the mRNA expression of G3BP1 and YB1 (YBX1) and their correlation in NSCLC. Also, expression of G3BP1, YB1, and p‐AKT proteins was studied using immunohistochemistry in tissue microarrays of NSCLC and in noncancerous lung tissues.ResultsWe found that the mRNA expression of G3BP1 and YB1 was higher in NSCLC tissues (both P < .05), and G3BP1 was positively correlated with YB1 in mRNA level (r = .399, P < .001). Also, expression of G3BP1, YB1, and p‐AKT proteins was higher in NSCLC tissues (all P < .05). And higher expression of G3BP1 and YB1 proteins was seen in patients with clinical stage II and III compared with stage I (both P < .05). Besides, expression of G3BP1 protein had a positive correlation with YB1 and p‐AKT (both P < .05). Moreover, overall survival was shorter in patients with overexpression of G3BP1, YB1, and p‐AKT proteins (all P < .05). Multivariate analysis confirmed that overexpression of G3BP1 protein was an independent poorer prognostic factor for NSCLC patients (P = .039).ConclusionG3BP1 may play a crucial role in activating PI3K/AKT/mTOR pathway. G3BP1 might be served as a novel prognostic biomarker for surgically resected NSCLC patients, which afforded new insights into the study on the mechanism and therapy of NSCLC.

In-house Implementation of Tumor Mutational Burden Testing to Predict Durable Clinical Benefit in Non-small Cell Lung Cancer and Melanoma Patients.

Tumor mutational burden (TMB) has emerged as an important potential biomarker for prediction of response to immune-checkpoint inhibitors (ICIs), notably in non-small cell lung cancer (NSCLC). However, its in-house assessment in routine clinical practice is currently challenging and validation is urgently needed. We have analyzed sixty NSCLC and thirty-six melanoma patients with ICI treatment, using the FoundationOne test (FO) in addition to in-house testing using the Oncomine TML (OTML) panel and evaluated the durable clinical benefit (DCB), defined by >6 months without progressive disease. Comparison of TMB values obtained by both tests demonstrated a high correlation in NSCLC (R2 = 0.73) and melanoma (R2 = 0.94). The association of TMB with DCB was comparable between OTML (area-under the curve (AUC) = 0.67) and FO (AUC = 0.71) in NSCLC. Median TMB was higher in the DCB cohort and progression-free survival (PFS) was prolonged in patients with high TMB (OTML HR = 0.35; FO HR = 0.45). In contrast, we detected no differences in PFS and median TMB in our melanoma cohort. Combining TMB with PD-L1 and CD8-expression by immunohistochemistry improved the predictive value. We conclude that in our cohort both approaches are equally able to assess TMB and to predict DCB in NSCLC.

Patient selection in non-small cell lung cancer: Histologic versus molecular subtypes?

Until recently, the selection of systemic therapy has not varied according to histologic subtypes of non-small cell lung cancer (NSCLC) and is largely empirical. Thus, the diagnosis of “non-smallcell lung cancer not otherwise specified” (NSCLC-NOS) has been a frequently-used, acceptable term for clinical decision-making, despite the fact that it is not recognized by the World Health Organization Classification of Lung Tumors (1). This paradigm has been challenged by new generation of rational cancer therapeutics. The first emphasis on histology in treatment decision in NSCLC came from safety concerns about the first-in-class angiogenesis inhibitor bevacizumab. A randomized Phase II trial of carboplatin and paclitaxel alone or with lowor high-dose bevacizumab revealed a severe (and even fatal) occurrence of pulmonary hemorrhage in NSCLC patients with squamous histology receiving bevacizumab (2). Thus, patients with squamous histology were subsequently excluded from Phase III trials of bevacizumab and most of anti-angiogenesis inhibitors in advanced NSCLC (3-6). The identification of molecularly-defined cohorts of NSCLC patients who demonstrate dramatic clinical response to targeted agents has changed the landscape of lung cancer therapy. An epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), gefinitb or gefitinib, was the first targeted therapy used for the treatment of NSCLC patients (7,8). Initial clinical experiences suggested that high tumor responses were observed among patients with adenocarcinoma and a light or never smoking history (9-11). These clinical observations led to the development of a Phase III trial of gefinitb compared with first-line chemotherapy doublets in this clinically selected patient population (12). Surprisingly, correlative molecular analyses in this Phase III study reveals that the key driver of response to EGFR TKIs is the presence of TK-activating EGFR mutations rather than histology, Asian ethnicity or clinical characteristics (13). The higher clinical responses observed in never or light smokers and NSCLC patients with adenocarcinoma rather than squamous histology are due to the higher prevalence of TK-activating EGFR mutations present in these patients. These results led to world-wide clinical testing for EGFR mutations for selecting those NSCLC patients for first-line therapy of an EGFR TKI in 2009 (14). Of note, papillary and micropapillary adenocarcinoma subtypes have been correlated with lung adenocarcinomas with EGFR mutations (15). However, the clinical value of subtyping histologic-genetic correlations in NSCLC remains to be determined as the genetic features for the majority of NSCLC have yet to be characterized and the histologic diagnosis of lung adenocarcinoma or squamous carcinoma could vary significantly between pathologists. Nevertheless, the cancer armentarium that might be selected by molecular biomarker status is quickly increasing. The echinoderm microtubule-

Correlation between OPN and P21 in non-small cell lung cancer

At present, little is known about the correlation between osteopontin (OPN) and P21 in primary non-small cell lung cancer (NSCLC). The aim of this study is to investigate the expression of OPN and P21 and their correlation in NSCLC. The expression of OPN and P21 was detected in 58 NSCLC tissues and 18 pulmonary inflammatory pseudotumor (PIP) as controls by immunohistochemical technique. The positive rate of OPN and P21 in NSCLC was 58.6% and 70.7% respectively, which was significantly higher than those in PIP (11.1% and 16.7%) (P=0.0008, P < 0.0001). There was a positive correlation between OPN and P21 expression (P < 0.0001). Lymph node metastasis was closely related to OPN expression (P=0.0367), but not to P21 expression (P=0.4898). The abnormal expression of OPN and P21 in NSCLC may act in a synergistic way. Immunopositivity of OPN may suggest a potential risk of metastasis in NSCLC.

Cyclooxygenase-2 protein levels are independent of epidermal growth factor receptor expression or activation in operable non-small cell lung cancer

Both cyclooxygenase (COX)-2 and epidermal growth factor receptor (EGFR) are thought to play important roles in the pathogenesis of non-small cell lung cancer (NSCLC). A number of in vitro studies have postulated a link between EGFR activation and subsequent COX-2 upregulation. The relationship between these factors has not been established in patients with NSCLC. COX-2 and EGFR expression were studied in 172 NSCLC specimens using standard immunohistochemical techniques. Western blotting was used to determine COX-2 and EGFR levels in five NSCLC cell lines. The effect of treatment with EGF on COX-2 expression in A549 cells was assessed. Both EGFR and COX-2 are overexpressed in NSCLC. The predominant pattern of COX-2 and EGFR staining was cytoplasmic. Membranous EGFR staining was seen in 23.3% of cases. There was no relationship between COX-2 and EGFR expression and survival or any clinicopathological features. No correlation was seen between EGFR expression and COX-2 expression in the immunohistochemical series or in the cell lines. Treatment with EGF did not upregulate COX-2 levels in A549 cells, either in serum free or serum-supplemented conditions. Although COX-2 and EGFR are over-expressed in NSCLC neither was of prognostic significance in this series of cases. There is no correlation between these two factors in either tumour samples or cell lines. Although these factors show no correlation in NSCLC, they remain potential, though independent targets for treatment.