scholarly journals ASCL1-regulated DARPP-32 and t-DARPP stimulate small cell lung cancer growth and neuroendocrine tumor cell survival

2019 ◽  
Author(s):  
Sk. Kayum Alam ◽  
Li Wang ◽  
Yanan Ren ◽  
Christina E. Hernandez ◽  
Farhad Kosari ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Tumor Tissue ◽  
Prognostic Indicator ◽  
Small Cell ◽  
Normal Lung ◽  
Sequencing Analysis ◽  
Small Cell Lung ◽  
Sclc Patient

AbstractSmall cell lung cancer (SCLC) is the most aggressive form of lung cancer, and new molecular insights are necessary for prognostic and therapeutic advances. Here we demonstrate in orthotopic mouse models that dopamine and cAMP-regulated phosphoprotein, Mr 32000 (DARPP-32) and its N-terminally truncated splice variant t-DARPP promote SCLC growth through increased proliferation, Akt/Erk-mediated survival and anti-apoptotic signaling. DARPP-32 and t-DARPP proteins are overexpressed in SCLC patient-derived tumor tissue, but virtually undetectable in physiologically normal lung. RNA sequencing analysis reveals a subset of SCLC patients with high tumoral t-DARPP expression and upregulated Notch signaling genes, including achaete-scute homologue 1 (ASCL1). We show that DARPP-32 isoforms are transcriptionally activated by ASCL1 in human SCLC cells. Taken together, we demonstrate new regulatory mechanisms of SCLC oncogenesis that suggest DARPP-32 isoforms may represent a negative prognostic indicator for SCLC and serve as a potential target for the development of new therapies.

Regenerating gene 1α (REG 1α) expression and new treatment strategies in early non-small cell lung cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22178-e22178
Author(s):  
T. Tojo ◽  
T. Tojo ◽  
H. Naito ◽  
M. Kimura ◽  
S. Takasawa ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Survival Rate ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Tumor Tissue ◽  
Small Cell ◽  
Normal Lung ◽  
Small Cell Lung ◽  
Total Rna ◽  
Reg Iα

e22178 Background: Regenerating gene (REG) I was originally isolated as an endogenous growth factor from pancreatic islet β cells. REG Iα protein is suggested to be involved in carcinogenesis in various gastroenterologic tissues. In the present study, to elucidate roles for REG Iα in non-small cell lung cancer (NSCLC), we investigated REG Iα expression in NSCLCs, focusing especially on its relationship with prognosis. Methods: We enrolled 70 NSCLCs (adenocarcinoma (AC)(n=48) and squamous cell carcinoma (SCC)(n=22)) who received surgery at Nara Medical University Hospital. Total RNA was extracted from each tumor tissue and corresponding normal lung tissue (NL)(n=70), cDNA was then reverse-transcribed from total RNA, and quantitative real-time reverse transcriptase-polymerase chain reaction was then carried out. The expression level of REG Iα in each sample was normalized with respect to that of β-actin, and the cutoff level was set at average+3SD expression of the 70 NLs. We also examined the relationship between REG 1α expression in the tumor tissue and the prognosis. Results: Six (12.5%) of the 48 ACs and 5 (22.7%) of the 22 SCCs were positive for REG Iα gene, and which is higher than that of NLs (2 of 70: 2.9%). After median follow-up of 26.2 months, 12 patients died due to disease progression. The survival rate among the REG 1α positive patients was significantly worse than among the REG 1α negative patients in ACs (P<0.05), and not significantly but worse in SCCs (P=0.07). In case of stage I, none of REG 1α negative patient died in both ACs and SCCs compared with 4 patients died of positive patients (AC:2, SCC:2), and also the survival rate among the REG 1α positive patients was significantly worse than among the negative patients in ACs (P<0.01) and SCCs (P<0.05). Disease free survival of REG 1α positive patients was also worse than negative patients in ACs (P<0.05) and SCCs (P=0.16). Conclusions: REG Iα expression in NSCLCs may be the risk factor for poor prognosis, and we anticipate that it will enable us to provide more appropriate and individualized treatment to patients of early NSCLC. No significant financial relationships to disclose.

The Key microRNAs Regulated the Development of Non-small Cell Lung Cancer by Targeting TGF-β-induced epithelial–mesenchymal Transition

2019 ◽  
Vol 22 (4) ◽  
pp. 238-244 ◽  
Author(s):  
Gang Chen ◽  
Bo Ye
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Nsclc Cell ◽  
Normal Lung ◽  
Migration And Invasion ◽  
Small Cell Lung ◽  
Mesenchymal Transition

Purpose: Epithelial-to-Mesenchymal Transition (EMT) was reported to play a key role in the development of Non-Small Cell Lung Cancer (NSCLC). The process of EMT is regulated by the changes of miRNAs expression. However, it is still unknown which miRNA changed the most in the process of canceration and whether these changes played a role in tumor development. Methods: A total of 36 SCLC patients treated in our hospital between 11th, 2015 and 10th, 2017 were enrolled. The samples of cancer tissues and paracancer tissues of patients were collected and analyzed. Then, the miRNAs in normal lung cells and NSCLC cells were also analyzed. In the presence of TGF-β, we transfected the miRNA mimics or inhibitor into NSCLC cells to investigate the role of the significantly altered miRNAs in cell migration and invasion and in the process of EMT. Results: MiR-330-3p was significantly up-regulated in NSCLC cell lines and tissues and miRNA- 205 was significantly down-regulated in NSCLC cell lines and NSCLC tissues. Transfected miRNA-205 mimics or miRMA-330-3p inhibitor inhibited the migration and invasion of NCIH1975 cell and restrained TGF-β-induced EMT in NSCLC cells. Conclusion: miRNA-330-3p and miRNA-205 changed the most in the process of canceration in NSCLC. Furthermore, miR-330-3p promoted cell invasion and metastasis in NSCLC probably by promoting EMT and miR-205 could restrain NSCLC likely by suppressing EMT.

scholarly journals Predicting ROR1/BCL2 combination targeted therapy of small cell carcinoma of the lung

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Walter Z. Wang ◽  
Konstantin Shilo ◽  
Joseph M. Amann ◽  
Alyssa Shulman ◽  
Mohammad Hojjat-Farsangi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cell Lung Cancer ◽  
Therapeutic Target ◽  
Small Cell ◽  
Orphan Receptor ◽  
Small Cell Lung ◽  
Sclc Patient

AbstractSmall cell lung cancer (SCLC) remains a deadly form of cancer, with a 5-year survival rate of less than 10 percent, necessitating novel therapies. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein that is emerging as a therapeutic target and is co-expressed with BCL2 in multiple tumor types due to microRNA coregulation. We hypothesize that ROR1-targeted therapy is effective in small cell lung cancer and synergizes with therapeutic BCL2 inhibition. Tissue microarrays (TMAs) and formalin-fixed paraffin-embedded (FFPE) SCLC patient samples were utilized to determine the prevalence of ROR1 and BCL2 expression in SCLC. Eight SCLC-derived cell lines were used to determine the antitumor activity of a small molecule ROR1 inhibitor (KAN0441571C) alone and in combination with the BCL2 inhibitor venetoclax. The Chou-Talalay method was utilized to determine synergy with the drug combination. ROR1 and BCL2 protein expression was identified in 93% (52/56) and 86% (48/56) of SCLC patient samples, respectively. Similarly, ROR1 and BCL2 were shown by qRT-PCR to have elevated expression in 79% (22/28) and 100% (28/28) of SCLC patient samples, respectively. KAN0441571C displayed efficacy in 8 SCLC cell lines, with an IC50 of 500 nM or less. Synergy as defined by a combination index of <1 via the Chou-Talalay method between KAN0441571C and venetoclax was demonstrated in 8 SCLC cell lines. We have shown that ROR1 inhibition is synergistic with BCL2 inhibition in SCLC models and shows promise as a novel therapeutic target in SCLC.

scholarly journals Interleukin-35 Expression in Non-Small Cell Lung Cancer is Associated with Tumor Progression

2018 ◽  
Vol 51 (4) ◽  
pp. 1839-1851 ◽  
Author(s):  
Mingfei Sun ◽  
Xianjie Zheng ◽  
Qingjiang Meng ◽  
Yanjun Dong ◽  
Guoyu Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Progression ◽  
Cell Lung Cancer ◽  
Disease Free Survival ◽  
Prognostic Indicator ◽  
Small Cell ◽  
Inflammatory Factor ◽  
Small Cell Lung ◽  
Chemotherapy Drugs

Background/Aims: Lung cancer continues to be the leading cause of cancer related deaths worldwide due to its high incidence, malignant behavior and lack of major advancements in treatment strategy. The occurrence and development of lung cancer is closely related to inflammation. Thus, we conducted the present study to investigate the effects of IL-35 (Interleukin 35), a newly identified anti-inflammatory factor, on non-small cell lung cancer (NSCLC), which accounts for about 85% of all lung cancers. Methods: We first evaluated the IL-35 expression in 384 pairs of NSCLC samples and their adjacent normal mucosa by realtime PCR, ELISA (Enzyme-linked immunoassay) and tissue microarrays. Then the role of IL-35 on patient survival rates, cancer progression and their sensitivity to chemotherapy drugs were assessed. Results: IL-35 was barely expressed in the NSCLC tissues but highly expressed in the adjacent normal tissues. The down-regulation of IL-35 was significantly correlated with the results of American Joint Committee on Cancer stage, differentiation and it was also shown to be an independent prognostic indicator of disease-free survival and overall survival for patients with NSCLC. Overexpression of IL-35 in NSCLC cells suppressed cell migration, invasion, proliferation, colony formation through suppressing β-catenin. IL-35 inhibited NSCLC formation in the mice model and sensitize the cancer cells to chemotherapy drugs. Conclusion: Our results showed that IL-35 plays an inhibitory role in NSCLC development and function as a novel prognostic indicator and a potential therapeutic target.

scholarly journals Kinesin superfamily protein 21B acts as an oncogene in non-small cell lung cancer

2020 ◽  
Author(s):  
Zhi-Gang Sun ◽  
Feng Pan ◽  
Jing-Bo Shao ◽  
Qian-Qian Yan ◽  
Lu Lu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Nude Mice ◽  
Cell Lung Cancer ◽  
A549 Cells ◽  
Small Cell ◽  
Normal Lung ◽  
Migration And Invasion ◽  
Small Cell Lung ◽  
Kinesin Superfamily

Abstract Background: Kinesin superfamily proteins (KIFs) serve as microtubule-dependent molecular motors, and are involved in the progression of many malignant tumors. In this study, we aimed to investigate the expression pattern and precise role of kinesin family member 21B (KIF21B) in non-small cell lung cancer (NSCLC). Methods: KIF21B expression in 72 cases of NSCLC tissues was measured by immunohistochemical staining (IHC). We used shRNA-KIF21B interference to silence KIF21B in NSCLC H1299 and A549 cells and normal lung epithelial bronchus BEAS-2B cells. The biological roles of KIF21B in the growth and metastasis abilities of NSCLC cells were measured by Cell Counting Kit-8 (CCK8), colony formation and Hoechst 33342/PI, wound-healing, and Transwell assays, respectively. Expression of apoptosis-related proteins was determined using western blot. The effect of KIF21B on tumor growth in vivo was examined using nude mice model. Results: KIF21B was up-regulated in NSCLC tissues, and correlated with pathological lymph node and pTNM stage, its high expression was predicted a poor prognosis of patients with NSCLC. Silencing of KIF21B mediated by lentivirus-delivered shRNA significantly inhibited the proliferation ability of H1299 and A549 cells. KIF21B knockdown increased apoptosis in H1299 and A549 cells, down-regulated the expression of Bcl-2 and up-regulated the expression of Bax and active Caspase 3. Moreover, KIF21B knockdown decreased the level of phosphorylated form of Akt (p-Akt) and Cyclin D1 expression in H1299 and A549 cells. In addition, silencing of KIF21B impeded the migration and invasion of H1299 and A549 cells. Further, silencing of KIF 21B dramatically inhibited xenograft growth in BALB/c nude mice. However, silencing of KIF21B did not affect the proliferation, migration and invasion of BEAS-2B cells.Conclusions: These results reveal that KIF21B is up-regulated in NSCLC and acts as an oncogene in the growth and metastasis of NSCLC, which may function as a potential therapeutic target and a prognostic biomarker for NSCLC.

scholarly journals MicroRNA-154 Expression is Associated With The Prognosis in Non-Small Cell Lung Cancer.

2020 ◽  
Author(s):  
Yue Zhao ◽  
Xiangjun Kong ◽  
Hongbing Wang
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Prognostic Indicator ◽  
Small Cell ◽  
Rank Test ◽  
Small Cell Lung ◽  
Lower Survival Rate ◽  
Nsclc Patients ◽  
Low Expression

Abstract Background: MicroRNAs are noncoding RNAs that regulate cellular processes during the progression of tumors. Among various microRNAs, MicroRNA-154 (miR-154) has been reported to be involved in many critical processes of human malignancies. This study aimed to evaluate the significance and prognostic value of miR-154 in human non-small cell lung cancer (NSCLC).Methods: A total of 144 NSCLC tissues samples and matched non-tumor adjacent tissues specimens were obtained from NSCLC patients and the quantitative real-time PCR (qRT-PCR) was performed to investigate expression levels of miR-154. The correlation between miR-154 expression and survival outcomes of NSCLC patients was performed by Kaplan-Meier analysis, univariate and multivariate analysis.Results: MiR-154 expression was significantly decreased in NSCLC tissues compared with that in matched non-tumor adjacent tissues (P<0.001). In addition, low expression of miR-154 was demonstrated to be associated with tumors size, TNM stages and distant metastasis of NSCLC patients Survival analysis revealed that patients with low expression of miR-154 showed significantly lower survival rate for OS, DFS and RFS, respectively (all, log rank test, P<0.001) and miR-154 could be an independent prognostic indicator for NSCLC patients.Conclusion: The results suggest that miR-154 has the clinical significance in the progression of NSCLC and could be a potential prognostic biomarker for NSCLC patients.

scholarly journals Pleural effusion as a substitute for tumor tissue in detecting EGFR/ALK mutations in non-small cell lung cancer

Medicine ◽  
2019 ◽  
Vol 98 (18) ◽  
pp. e15450 ◽  
Author(s):  
Caishuang Pang ◽  
Huiwen Ma ◽  
Jiangyue Qin ◽  
Sixiong Wang ◽  
Chun Wan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Pleural Effusion ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Tumor Tissue ◽  
Small Cell ◽  
Small Cell Lung
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