Potential Of Lung Adenocarcinoma Cells Research Articles

SETDB1 fuels the lung cancer phenotype by modulating epigenome, 3D genome organization and chromatin mechanical properties.

Imbalance in the finely orchestrated system of chromatin-modifying enzymes is a hallmark of many pathologies such as cancers, since causing the affection of the epigenome and transcriptional reprogramming. Here, we demonstrate that a loss-of-function mutation (LOF) of the major histone lysine methyltransferase SETDB1 possessing oncogenic activity in lung cancer cells leads to broad changes in the overall architecture and mechanical properties of the nucleus through genome-wide redistribution of heterochromatin, which perturbs chromatin spatial compartmentalization. Together with the enforced activation of the epithelial expression program, cytoskeleton remodeling, reduced proliferation rate and restricted cellular migration, this leads to the reversed oncogenic potential of lung adenocarcinoma cells. These results emphasize an essential role of chromatin architecture in the determination of oncogenic programs and illustrate a relationship between gene expression, epigenome, 3D genome and nuclear mechanics.

MiR-24-3p/FGFR3 Signaling as a Novel Axis Is Involved in Epithelial-Mesenchymal Transition and Regulates Lung Adenocarcinoma Progression.

Our previous studies showed that Fibroblast growth factor receptor 3 (FGFR3) contributed to cell growth in lung cancer. However, the correlation between FGFR3 and tumor progression, coupled with the underlying mechanisms, are not fully understood. The clinical significance of FGFR3 was determined in two cohorts of clinical samples (n = 22, n = 78). A panel of biochemical assays and functional experiments was utilized to elucidate the underlying mechanisms and effects of FGFR3 and miR-24-3p on lung adenocarcinoma progression. Upregulated FGFR3 expression indicated an adverse prognosis for lung adenocarcinoma individuals and promoted metastatic potential of lung adenocarcinoma cells. Owing to the direct regulation towards FGFR3, miR-24-3p could interfere with the potential of proliferation, migration, and invasion in lung adenocarcinoma, following variations of EMT-related protein expression. As a significant marker of EMT, E-cadherin was negatively correlated with FGFR3, of which ectopic overexpression could neutralize the antitumour effects of miR-24-3p and reverse its regulatory effects on EMT markers. Taken together, these findings define a novel insight into the miR-24-3p/FGFR3 signaling axis in regulating lung adenocarcinoma progression and suggest that targeting the miR-24-3p/FGFR3 axis could be an effective and efficient way to prevent tumor progression.

Claudin-3 expression increases the malignant potential of lung adenocarcinoma cells: role of epidermal growth factor receptor activation.

Claudins are essential for the formation and maintenance of tight junctions (TJ). The altered expression of claudin proteins has been described in a variety of malignancies. However, the alteration of these proteins in lung adenocarcinoma (ADC) are poorly understood. Therefore, we report, based on the protein expression analysis of a total of 275 patient samples, that claudin-3 (CLDN3) expression is significantly increased in ADC tissues and is associated with cancer progression, correlating significantly with the poor survival of ADC patients (p=0.041&0.029). More importantly, forcing CLDN3 expression in ADC cells without endogenous CLDN3 expression resulted in significant increases in the cell proliferation, anchorage-dependent growth, migration and drug-resistance. In addition, epidermal growth factor (EGF) signaling pathway modulates the expression of claudins in a number of solid tumors. However, the mechanism of tight junction regulation by EGF in ADC remains unclear. To investigate this mechanisms, ADC cell lines were treated with EGF and its inhibitor. EGF unregulated CLDN3 expression via the MEK/ERK or PI3K/Akt signaling pathways and was required for the maintenance of baseline CLDN3 expression. Furthermore, downregulation of CLDN3 expression in ADC cell was found to prevent the EGF-induced increase in cell proliferation. In conclusion, our results demonstrate a novel role of CLDN3 overexpression in promoting the malignant potential of lung adenocarcinoma. This function is potentially regulated by the EGF-activated MEK/ERK and PI3K-Akt pathways.

PARP1 enhances lung adenocarcinoma metastasis by novel mechanisms independent of DNA repair.

The role of poly (ADP-ribose) polymerase 1 (PARP1) in cancer has been extensively studied in the context of DNA repair, leading to clinical trials of PARP1 inhibitors in cancers defective in homologous recombination. However, the DNA repair-independent roles of PARP1 in carcinogenesis and metastasis, particularly in lung cancer metastasis, remain largely uncharacterized. Here, we report that PARP1 promotes lung adenocarcinoma relapse to the brain and bones by regulating several steps of the metastatic process in a DNA repair-independent manner. We find that PARP1 expression is associated with overall and distant metastasis-free survival in lung adenocarcinoma patients. Consistent with this, genetic knockdown and pharmacological inhibition of PARP1 significantly attenuated the metastatic potential of lung adenocarcinoma cells. Further investigation revealed that PARP1 potentiates lung adenocarcinoma metastasis by promoting invasion, anoikis resistance, extravasation and self-renewal of lung adenocarcinoma cells and also by modifying the brain microenvironment. Finally, we identified S100A4 and CLDN7 as novel transcriptional targets and clinically relevant effectors of PARP1. Collectively, our study not only revealed previously unknown functions of PARP1 in lung adenocarcinoma metastasis but also delineated the molecular mechanisms underlying the pro-metastatic function of PARP1. Furthermore, these findings provide a foundation for the potential use of PARP1 inhibitors as a new treatment option for lung adenocarcinoma patients with elevated PARP1 expression.

Silencing of the human TERT gene by RNAi inhibits A549 lung adenocarcinoma cell growth in vitro and in vivo

Human telomerase reverse transcriptase (hTERT) is the catalytic subunit and the activity determinant factor of the telomerase enzyme which maintains the length of human chromosomes. In recent years it has become an attractive molecular target for cancer gene therapy. In the present study, we show that hTERT siRNA effectively suppressed the expression of hTERT mRNA and hTERT protein levels, reduced telomerase activity, and induced apoptosis of A549 lung adenocarcinoma cells (P<0.05). Invivo, tumors treated with the hTERT siRNA were of reduced sizes, indicating that the hTERT siRNA also reduced the tumorigenic potential of lung adenocarcinoma cells (P<0.05). These results demonstrate that hTERT siRNA can cause effective suppression of telomerase and lead to apoptosis in A549 lung adenocarcinoma cells. hTERT siRNA may, therefore, be a strong candidate for highly selective therapy for chemoprevention and treatment of lung adenocarcinoma.

Functional role of inositol‐1,4,5‐trisphosphate‐3‐kinase‐A for motility of malignant transformed cells

Cell migration is one of the hallmarks of metastatic disease and thus identification of migration promoting proteins is crucial for the understanding of metastasis formation. Here we show that the neuron-specific, F-actin bundling inositol-1,4,5-trisphosphate-3-kinase-A (ITPKA) is ectopically expressed in tumor cells and critically involved in migration. Down-regulation of ITPKA expression in transformed cell-lines with ectopic expression of ITPKA significantly decreased migration and the number of linear and branched cell protrusion. Conversely, up-regulation of ITPKA in tumor cell lines with low endogenous ITPKA expression increased migration and formation of cell processes. In vitro, ITPKA alone induced the formation of linear actin filaments, whereas ITPKA mediated formation of branched protrusions seems to result from interaction between ITPKA and the F-actin cross-linking protein filamin C. Based on these actin-modulating and migration-promoting effects of ITPKA we examined its expression in clinical samples of different tumor entities, starting with the analysis of multiple tumor tissue arrays. As in lung adenocarcinoma specimens, the highest ITPKA expression rate was found, this tumor entity was examined in more detail. ITPKA was expressed early in adenocarcinoma progression (pN0) and was largely maintained in invasive and metastatic tumor cell populations (pN1/2, lymph node metastases). Together with our result that high expression of ITPKA increases motility of tumor cells we conclude that the observed expression of ITPKA early in tumor development increases the metastatic potential of lung adenocarcinoma cells. Therefore, we suggest that ITPKA may be a promising therapeutic molecular target for anti metastatic therapy of lung cancer.

Benzo[a]pyrene promotes proliferation of human lung cancer cells by accelerating the epidermal growth factor receptor signaling pathway

Smoking is an independent prognostic factor of lung adenocarcinoma. Benzo[a]pyrene (B[a]P) is one of the strongest carcinogens and it is present in both the environment and cigarette smoke. In this study, the effect of B[a]P on the proliferative activity of lung adenocarcinoma cells was investigated. A lung adenocarcinoma cell line, A549, was cultured with B[a]P for various periods, and its proliferative activity was examined by an MTS assay. To investigate the intracellular events related to the proliferative activity, the gene expression profile was investigated by a microarray analysis and a quantitative RT-PCR, and the protein expression and activation status of Akt, ERK 1/2 and the epidermal growth factor receptor (EGFR) were examined by a western blot analysis. Following the culture with B[a]P for 24 weeks, the serum-independent proliferative activity was increased. A microarray analysis revealed that a reversible upregulation of the EGFR and epiregulin genes was recognized in the B[a]P treated cells, in which the overexpression of the phosphorylated EGFR protein was also recognized. The EGFR tyrosine kinase inhibitor reduced the cellular proliferation and the level of phosphorylation of ERK1/2, which is a downstream signal of the EGFR, in the B[a]P-treated A549 cells. Moreover, the B[a]P treatment increased the mRNA expressions of the ligands for EGFR such as amphiregulin and epiregulin. B[a]P increases the proliferative potential of lung adenocarcinoma cells through the EGFR signaling pathway.