scholarly journals Intrachromosomal rearrangements fusing L-myc and rlf in small-cell lung cancer.

1991 ◽  
Vol 11 (8) ◽  
pp. 4015-4021 ◽  
Author(s):  
T P Mäkelä ◽  
J Kere ◽  
R Winqvist ◽  
K Alitalo
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Human Cancer ◽  
Small Cell ◽  
Chromosome 1 ◽  
Small Cell Lung ◽  
Amino Terminal ◽  
Myc Gene ◽  
Intrachromosomal Rearrangements

Chromosomal abnormalities affecting proto-oncogenes are frequently detected in human cancer. Oncogenes of the myc family are activated in several types of tumors as a result of gene amplification or chromosomal translocation. We have recently found the L-myc gene involved in a gene fusion in small-cell lung cancer (SCLC). This results in a chimeric protein with amino-terminal sequences from a novel gene named rif joined to L-myc. Here we present a preliminary structural characterization of the rlf-L-myc fusion gene, which has been found only in cells with an amplified L-myc gene. In addition, we have used somatic cell hybrids to assign the normal rlf locus to the same chromosome (chromosome 1) on which L-myc resides. Finally, we have been able to establish a physical linkage between rif and L-myc with pulsed-field gel electrophoresis. Our results demonstrate that normal rlf and L-myc genes are separated by less than 800 kb of DNA. Thus, the rlf-L-myc gene fusions are due to similar but not identical intrachromosomal rearrangements at 1p32. The presence of independent genetic lesions that cause the formation of identical chimeric rlf-L-myc proteins suggests a role for the fusion protein in the development of these tumors.

Intrachromosomal rearrangements fusing L-myc and rlf in small-cell lung cancer

1991 ◽  
Vol 11 (8) ◽  
pp. 4015-4021
Author(s):  
T P Mäkelä ◽  
J Kere ◽  
R Winqvist ◽  
K Alitalo
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Human Cancer ◽  
Small Cell ◽  
Chromosome 1 ◽  
Small Cell Lung ◽  
Amino Terminal ◽  
Myc Gene ◽  
Intrachromosomal Rearrangements

Chromosomal abnormalities affecting proto-oncogenes are frequently detected in human cancer. Oncogenes of the myc family are activated in several types of tumors as a result of gene amplification or chromosomal translocation. We have recently found the L-myc gene involved in a gene fusion in small-cell lung cancer (SCLC). This results in a chimeric protein with amino-terminal sequences from a novel gene named rif joined to L-myc. Here we present a preliminary structural characterization of the rlf-L-myc fusion gene, which has been found only in cells with an amplified L-myc gene. In addition, we have used somatic cell hybrids to assign the normal rlf locus to the same chromosome (chromosome 1) on which L-myc resides. Finally, we have been able to establish a physical linkage between rif and L-myc with pulsed-field gel electrophoresis. Our results demonstrate that normal rlf and L-myc genes are separated by less than 800 kb of DNA. Thus, the rlf-L-myc gene fusions are due to similar but not identical intrachromosomal rearrangements at 1p32. The presence of independent genetic lesions that cause the formation of identical chimeric rlf-L-myc proteins suggests a role for the fusion protein in the development of these tumors.

scholarly journals Long Noncoding RNA FAL1 Promotes Cell Proliferation, Invasion and Epithelial-Mesenchymal Transition Through the PTEN/AKT Signaling Axis in Non-Small Cell Lung Cancer

2017 ◽  
Vol 43 (1) ◽  
pp. 339-352 ◽  
Author(s):  
Chunfeng Pan ◽  
Guoliang Yao ◽  
Bin Liu ◽  
Teng Ma ◽  
Yang Xia ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Noncoding Rna ◽  
Biological Effects ◽  
Small Cell ◽  
Chromosome 1 ◽  
Small Cell Lung ◽  
Mesenchymal Transition

Background/Aims: Recently, long non-coding RNAs (lncRNAs) have been found to have many biological effects in different cancer stages. Several studies have revealed that focally amplified lncRNA on chromosome 1 (FAL1) regulates cancer progression via p21. However, the expression and mechanism of FAL1 in non-small cell lung cancer (NSCLC) still remain unclear. Methods: We detected the FAL1 level in NSCLC tissues and in established cell lines using quantitative real-time PCR and evaluated the clinical significance. FAL1 was silenced or overexpressed using siRNA or lentivirus to study whether FAL1 affected cell proliferation, invasion and migration. Xenograft growth and pulmonary metastasis were observed using nude mouse models. The mechanisms were explored with western blotting and immunohistochemistry. Results: FAL1 was significantly overexpressed in NSCLC compared with adjacent normal tissues, and a high level of FAL1 correlated with poor histological grade, increased lymph node metastasis and advanced TNM stage. Loss- and gain-of-function experiments in vitro verified that knockdown of FAL1 inhibited cell proliferation, invasion, migration and EMT via the PTEN/AKT pathway. Furthermore, an in vivo assay confirmed that overexpression of FAL1 facilitated tumor growth and metastasis. Conclusion: FAL1 may promote tumorigenesis and progression of NSCLC through the PTEN/AKT axis, which could lead to lncRNA-related diagnostics and therapeutics in NSCLC.

Structure and expression of the human L-myc gene reveal a complex pattern of alternative mRNA processing

1988 ◽  
Vol 8 (1) ◽  
pp. 186-195
Author(s):  
F Kaye ◽  
J Battey ◽  
M Nau ◽  
B Brooks ◽  
E Seifter ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Lung Cancer ◽  
Cancer Cell Lines ◽  
Small Cell ◽  
Lung Cancer Cell ◽  
Small Cell Lung ◽  
Myc Gene

We analyzed in detail the structure of the L-myc gene isolated from human placental DNA and characterized its expression in several small-cell lung cancer cell lines. The gene is composed of three exons and two introns spanning 6.6 kilobases in human DNA. Several distinct mRNA species are produced in all small-cell lung cancer cell lines that express L-myc. These transcripts are generated from a single gene by alternative splicing of introns 1 and 2 and by use of alternative polyadenylation signals. In some mRNAs there is a long open reading frame with a predicted translated protein of 364 residues. Amino acid sequence comparison with c-myc and N-myc demonstrated multiple discrete regions with extensive homology. In contrast, other mRNA transcripts, generated by alternative processing, could encode a truncated protein with a novel carboxy-terminal end.

scholarly journals Deep sequencing of the TP53 gene reveals a potential risk allele for non–small cell lung cancer and supports the negative prognostic value of TP53 variants

Tumor Biology ◽  
2017 ◽  
Vol 39 (2) ◽  
pp. 101042831769432 ◽  
Author(s):  
Christophe Deben ◽  
Jolien Van den Bossche ◽  
Nele Van Der Steen ◽  
Filip Lardon ◽  
An Wouters ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Deep Sequencing ◽  
Cell Lung Cancer ◽  
Prognostic Value ◽  
Human Cancer ◽  
Tp53 Gene ◽  
Small Cell ◽  
Small Cell Lung ◽  
Tp53 Mutations

The TP53 gene remains the most frequently altered gene in human cancer, of which variants are associated with cancer risk, therapy resistance, and poor prognosis in several tumor types. To determine the true prognostic value of TP53 variants in non–small cell lung cancer, this study conducted further research, particularly focusing on subtype and tumor stage. Therefore, we determined the TP53 status of 97 non–small cell lung cancer adenocarcinoma patients using next generation deep sequencing technology and defined the prognostic value of frequently occurring single nucleotide polymorphisms and mutations in the TP53 gene. Inactivating TP53 mutations acted as a predictor for both worse overall and progression-free survival in stage II–IV patients and patients treated with DNA-damaging (neo)adjuvant therapy. In stage I tumors, the Pro-allele of the TP53 R72P polymorphism acted as a predictor for worse overall survival. In addition, we detected the rare R213R (rs1800372, minor allele frequency: 0.0054) polymorphism in 7.2% of the patients and are the first to show the significant association with TP53 mutations in non–small cell lung cancer adenocarcinoma patients (p = 0.003). In conclusion, Our findings show an important role for TP53 variants as negative predictors for the outcome of non–small cell lung cancer adenocarcinoma patients, especially for TP53 inactivating mutations in advanced stage tumors treated with DNA-damaging agents, and provide the first evidence of the R213R G-allele as possible risk factor for non–small cell lung cancer.

scholarly journals Complex intrachromosomal rearrangement in the process of amplification of the L-myc gene in small-cell lung cancer.

1992 ◽  
Vol 12 (4) ◽  
pp. 1747-1754 ◽  
Author(s):  
Y Sekido ◽  
T Takahashi ◽  
T P Mäkelä ◽  
Y Obata ◽  
R Ueda ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Line ◽  
Cell Lung Cancer ◽  
Sequence Similarity ◽  
Dna Amplification ◽  
Small Cell ◽  
Small Cell Lung ◽  
Range Analysis ◽  
Myc Gene

The L-myc gene was first isolated from a human small-cell lung cancer (SCLC) cell line on the basis of its amplification and sequence similarity to c-myc and N-myc. A new mechanism of L-myc activation which results from the production of rlf-L-myc fusion protein was recently reported. On the basis of our earlier observation of a rearrangement involving amplified L-myc in an SCLC cell line, ACC-LC-49, we decided to investigate this rearrangement in detail along with the structure of L-myc amplification units in five additional SCLC cell lines. We report here the identification of a novel genomic region, termed jal, which is distinct from rlf and is juxtaposed to and amplified with L-myc during the process of DNA amplification of the region encompassing L-myc. Long-range analysis using pulsed-field gel electrophoresis revealed that the amplified L-myc locus is involved in highly complex intrachromosomal rearrangements with jal and/or rlf. Our results also suggest that the simultaneous presence of rearrangements both in rlf intron 1 and in regions immediately upstream of L-myc may be necessary for the expression of rlf-L-myc chimeric transcripts.

scholarly journals Multiple mechanisms for transcriptional regulation of the myc gene family in small-cell lung cancer.

1988 ◽  
Vol 8 (8) ◽  
pp. 3373-3381 ◽  
Author(s):  
G Krystal ◽  
M Birrer ◽  
J Way ◽  
M Nau ◽  
E Sausville ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Gene Family ◽  
Gene Amplification ◽  
Cell Lung Cancer ◽  
Promoter Activity ◽  
Small Cell ◽  
Mrna Levels ◽  
Small Cell Lung ◽  
Myc Gene

The molecular mechanisms reported to regulate the expression of myc family genes are multiple and complex and include gene amplification, transcriptional activation, transcriptional attenuation, and mRNA stability. We have investigated which of these mechanisms are responsible for the extreme variation in myc gene family mRNA levels observed in human small-cell lung cancer cell lines. In addition to gene amplification, a block to nascent mRNA chain elongation, causing attenuation of transcription, is an important regulatory mechanism controlling the steady-state levels of c-myc and L-myc mRNA. The loss of transcriptional attenuation is correlated with overexpression of these two genes in cell lines which do not show gene amplification. Expression of c-myc mRNA appears to be dependent on promoter activity and attenuator function. In contrast, regulation of expression of the N-myc gene does not involve transcriptional attenuation; steady-state mRNA levels are correlated with promoter activity as well as gene amplification. We conclude that transcriptional regulation of each member of the myc gene family is accomplished by a different assortment of complex mechanisms, including gene copy number, promoter activation, and transcriptional attenuation. Interference at multiple points in this complex regulatory process appears to be an important mechanism by which small-cell lung cancer and other human tumors evade growth control.

scholarly journals Axon-like protrusions promote small cell lung cancer migration and metastasis

2019 ◽  
Author(s):  
Dian Yang ◽  
Fangfei Qu ◽  
Hongchen Cai ◽  
Chen-Hua Chuang ◽  
Jing Shan Lim ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Human Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Neuroblast Migration ◽  
Cancer Migration ◽  
Neuronal Gene

SUMMARYMetastasis is the main cause of death in cancer patients but remains a poorly understood process. Small cell lung cancer (SCLC) is one of the most lethal and most metastatic types of human cancer. SCLC cells normally express neuroendocrine and neuronal gene programs but accumulating evidence indicates that these cancer cells become relatively more neuronal and less neuroendocrine as they gain the ability to metastasize. Here we show that mouse and human SCLC cells in culture and in vivo can grow cellular protrusions that resemble axons. The formation of these protrusions is controlled by multiple neuronal factors implicated in axonogenesis, axon guidance, and neuroblast migration. Disruption of these axon-like protrusions impairs cell migration in culture and inhibits metastatic ability in vivo. The co-option of developmental neuronal programs is a novel molecular and cellular mechanism that contributes to the high metastatic ability of SCLC.

scholarly journals Discovery of SIPI6473, a New, Potent, and Orally Bioavailable Multikinase Inhibitor for the Treatment of Non-small Cell Lung Cancer

2021 ◽  
Vol 03 (01) ◽  
pp. e1-e7
Author(s):  
Xiu Gu ◽  
Zi-Xue Zhang ◽  
Min-Ru Jiao ◽  
Xin-Yan Peng ◽  
Jian-Qi Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Human Cancer ◽  
Xenograft Model ◽  
Small Cell ◽  
Maximum Effect ◽  
Small Cell Lung ◽  
Multikinase Inhibitor

A novel series of quinazoline derivatives were designed, synthesized, and evaluated as multikinase inhibitors. Most of these compounds showed antiproliferation activities of several human cancer cell lines and exhibited inhibition efficacy against the estimated glomerular filtration rate (EGFR) in the nanomolar level. Among those compounds, compound B5 (also named SIPI6473) displayed the maximum effect, and thus was chosen for further study. Our data revealed that B5 inhibited the activity of several kinases (such as EGFR, VEGFR2, and PDGFRα) that contributed to the development of non-small cell lung cancer (NSCLC). Besides, an in vivo study also showed that B5 inhibited tumor growth without signs of adverse effects in the A549 xenograft model. In conclusion, B5 may represent a new and promising drug for the treatment of NSCLC.

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