Small cell lung cancer (SCLC) is an aggressive disease characterized by rapid growth and metastases. It has been recognized that the inflammation of the microenvironment plays a critical role in the development of malignancies. However, little is known about the role of multiple inflammatory and hematological markers in the prognosis of SCLC. The aim of this study was to determine the clinical significance of pre-treatment inflammation-based scores and characteristics as prognostic indicators for the survival of SCLC patients. A retrospective analysis of 919 SCLC cases was performed. Patients' characteristics and hematologic tests data at initial diagnosis were collected. The univariate analysis of all SCLC patients indicated that favorable prognostic factors were age ˂ 70 years, non-smokers, good performance status, limited disease and response to treatment. Moreover, univariate analysis of inflammation-based scores and other blood parameters showed that neutrophil-lymphocyte ratio ≥ 5, platelet-lymphocyte ratio ≥ 250, systemic immune-inflammation index (SII) ≥ 1,600 × 10 9 /L, prognostic nutritional index (albumin + 5 × lymphocyte) < 45, and elevated serum lactate dehydrogenase (LDH) predicted poor prognosis in SCLC patients. SII represents the score that is calculated as follows: platelet count × neutrophil count/lymphocyte count. In the multivariate analysis, SII, together with serum LDH, stage and response to therapy, were associated with overall survival (OS). This study demonstrated that the combination of platelet count and neutrophil-lymphocyte ratio could help to predict poor prognosis in SCLC. Our findings will facilitate the understanding of survival differences in SCLC patients in clinical practice.
SUMMARY
Multiple mechanisms of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been identified in EGFR-mutant non-small cell lung cancer (NSCLC); however, recurrent resistance to EGFR TKIs due to the heterogeneous mechanisms underlying resistance within a single patient remains a major challenge in the clinic. Here, we report a role of nuclear protein kinase Cδ (PKCδ) as a common axis across multiple known TKI-resistance mechanisms. Specifically, we demonstrate that TKI-inactivated EGFR dimerizes with other membrane receptors implicated in TKI resistance to promote PKCδ nuclear translocation. Moreover, the level of nuclear PKCδ is associated with TKI response in patients. The combined inhibition of PKCδ and EGFR induces marked regression of resistant NSCLC tumors with EGFR mutations.
Human non-small cell lung carcinoma (NSCLC) is one of the most common cancer worldwide. In previous studies, lovastatin, acting as an inhibitor of 3-hydroxy-3-methylglutaryl Co A (HMG-CoA) reductase, exhibited significant antitumor activity during tumorigenesis. However, whether or not this effect is mediated through changes in minichromosome maintenance (MCM) 2 expression remains unclear. The present study investigated whether lovastatin inhibits proliferation due to MCM2 in NSCLCs. We first assessed the effects of lovastatin on cell anti-proliferation, cell cycle progression and apoptosis in NSCLC cells. We found, by quantitative RT-PCR and western blot analysis, that lovastatin treatment markedly and consistently inhibited the expression of MCM2. Then, to further explore the anticancer mechanism of lovastatin involving MCM2, we silenced MCM2 by siRNA in two cell lines (A549 and GLC-82). Silencing of MCM2 triggered G1/S arrest. Following further examination of cell cycle-related factors, MCM2 knockdown inhibited protein retinoblastoma (Rb), cyclin D1 and CDK4 expression, but increased p21 and p53 expression, suggesting that siMCM2 indeed triggered cell cycle arrest. In addition, siMCM2 induced apoptosis. Finally, lovastatin treatment increased p-JNK, which is involved in the downregulation of MCM2. In conclusion, our data suggest that MCM2 may be a novel therapeutic target of lovastatin treatment in NSCLCs.
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