Distinct transcriptional programs of SOX2 in different types of small cell lung cancers

Tenjin, Yuki; Matsuura, Kazuki; Kudoh, Shinji; Usuki, Shingo; Yamada, Tatsuya; Matsuo, Akira; Sato, Younosuke; Saito, Hiuga; Fujita, Kosuke; Wakimoto, Joeji; Ichimura, Tsuyoshi; Kohrogi, Hirotsugu; Sakagami, Takuro; Niwa, Hitoshi; Ito, Takaaki

doi:10.1038/s41374-020-00479-0

Cited by 13 publications

(18 citation statements)

References 43 publications

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“…The positive expression rates of ASCL1 and NEUROD1 in our SCLC samples were similar to those found in previous reports [22,27]. The expression of the target molecules in the ASCL1-positive group was consistent with previous findings [31,[33][34][35][36][37][38][39][40][41][42]. As half of the candidate ASCL1-target molecules selected from the gene expression omnibus dataset showed significance in the IHC study of the ASCL1-positive samples, IHC could be a useful method for detecting candidate target molecules for the four key molecules.…”

Section: Discussionsupporting

confidence: 93%

“…The expression of SOX2, TTF1, EZH2, DLL3, and TEAD1 was significantly upregulated in the ASCL1-positive group. SOX2 is a transcriptional regulator of neuroendocrine differentiation [31,33], and TTF1 is expressed in club, alveolar type II, and bronchial neuroendocrine cells [34]. A previous study reported that the expression of EZH2 promoted the progression of SCLC by suppressing the TGF-β-SMAD-ASCL1 pathway [35], while the expression of DLL3 was positively correlated with that of ASCL1 in SCLC [36].…”

Section: Discussionmentioning

confidence: 99%

“…The POU2F3-positive group appeared to correspond to the non-neuroendocrine group of SCLC based on the significant decrease observed in INSM1 expression. INSM1 is a highly sensitive and specific marker of neuroendocrine differentiation [14,15], and a strong correlation between the expression of ASCL1 and INSM1 in neuroendocrine differentiation has been reported [30][31][32]. NEUROD1-positive SCLC is another neuroendocrine subtype of SCLC; however, no significant differences in the expression of general neuroendocrine markers between the NEUROD1-positive and NEUROD1-negative groups were noted.…”

Section: Discussionmentioning

confidence: 99%

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Integrated Immunohistochemical Study on Small-Cell Carcinoma of the Lung Focusing on Transcription and Co-Transcription Factors

et al. 2020

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Small-cell lung cancer (SCLC) is an aggressive malignant cancer that is classified into four subtypes based on the expression of the following key transcription and co-transcription factors: ASCL1, NEUROD1, YAP1, and POU2F3. The protein expression levels of these key molecules may be important for the formation of SCLC characteristics in a molecular subtype-specific manner. We expect that immunohistochemistry (IHC) of these molecules may facilitate the diagnosis of the specific SCLC molecular subtype and aid in the appropriate selection of individualized treatments. We attempted IHC of the four key factors and 26 candidate SCLC target molecules selected from the gene expression omnibus datasets of 47 SCLC samples, which were grouped based on positive or negative results for the four key molecules. We examined differences in the expression levels of the candidate targets and key molecules. ASCL1 showed the highest positive rate in SCLC samples, and significant differences were observed in the expression levels of some target molecules between the ASCL1-positive and ASCL1-negative groups. Furthermore, the four key molecules were coordinately and simultaneously expressed in SCLC cells. An IHC study of ASCL1-positive samples showed many candidate SCLC target molecules, and IHC could become an essential method for determining SCLC molecular subtypes.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Integrated Immunohistochemical Study on Small-Cell Carcinoma of the Lung Focusing on Transcription and Co-Transcription Factors

et al. 2020

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“…The high expression of these lncRNAs was accompanied with the upregulation of coding genes such as C4A and C4B in the maturation stage, both of which are hub genes (kME > 0.94) in a module associated with maturation. Furthermore, the alteration of LINC00261, C4A, and C4B following valproic acid treatment in motor neurons ( Yoshida et al, 2015 ), as well as the clustering of AC025280.2 with neuron-related genes ( Tenjin et al, 2020 ), suggest the possible role of these genes in neuron development. Additionally, while the expression and function of GAS6-DT in neurons and the brain remain unclear, there is evidence that GAS6-DT is involved in the upregulation of GAS6 gene expression in melanomas ( Wen et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

Transcriptome Dynamics of Human Neuronal Differentiation From iPSC

Kuruş

Akbari

Eskier

et al. 2021

Front. Cell Dev. Biol.

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The generation and use of induced pluripotent stem cells (iPSCs) in order to obtain all differentiated adult cell morphologies without requiring embryonic stem cells is one of the most important discoveries in molecular biology. Among the uses of iPSCs is the generation of neuron cells and organoids to study the biological cues underlying neuronal and brain development, in addition to neurological diseases. These iPSC-derived neuronal differentiation models allow us to examine the gene regulatory factors involved in such processes. Among these regulatory factors are long non-coding RNAs (lncRNAs), genes that are transcribed from the genome and have key biological functions in establishing phenotypes, but are frequently not included in studies focusing on protein coding genes. Here, we provide a comprehensive analysis and overview of the coding and non-coding transcriptome during multiple stages of the iPSC-derived neuronal differentiation process using RNA-seq. We identify previously unannotated lncRNAs via genome-guided de novo transcriptome assembly, and the distinct characteristics of the transcriptome during each stage, including differentially expressed and stage specific genes. We further identify key genes of the human neuronal differentiation network, representing novel candidates likely to have critical roles in neurogenesis using coexpression network analysis. Our findings provide a valuable resource for future studies on neuronal differentiation.

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“…2c ). SOX2 and INSM1 are frequently expressed in MCC and other neuroendocrine tumors and are regarded as markers for a neuroendocrine phenotype [ 27 – 29 ]. Analysis of all CpGs with annotations for INSM1 and SOX2-OT revealed that hypermethylation was evident in all UV-MCC and vMCC cell lines (Fig.…”

Section: Resultsmentioning

confidence: 99%

DNA-methylation patterns imply a common cellular origin of virus- and UV-associated Merkel cell carcinoma

et al. 2021

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Merkel cell carcinoma (MCC) is a neuroendocrine tumor either induced by integration of the Merkel cell polyomavirus into the cell genome or by accumulation of UV-light-associated mutations (VP-MCC and UV-MCC). Whether VP- and UV-MCC have the same or different cellular origins is unclear; with mesenchymal or epidermal origins discussed. DNA-methylation patterns have a proven utility in determining cellular origins of cancers. Therefore, we used this approach to uncover evidence regarding the cell of origin of classical VP- and UV-MCC cell lines, i.e., cell lines with a neuroendocrine growth pattern (n = 9 and n = 4, respectively). Surprisingly, we observed high global similarities in the DNA-methylation of UV- and VP-MCC cell lines. CpGs of lower methylation in VP-MCC cell lines were associated with neuroendocrine marker genes such as SOX2 and INSM1, or linked to binding sites of EZH2 and SUZ12 of the polycomb repressive complex 2, i.e., genes with an impact on carcinogenesis and differentiation of neuroendocrine cancers. Thus, the observed differences appear to be rooted in viral compared to mutation-driven carcinogenesis rather than distinct cells of origin. To test this hypothesis, we used principal component analysis, to compare DNA-methylation data from different epithelial and non-epithelial neuroendocrine cancers and established a scoring model for epithelial and neuroendocrine characteristics. Subsequently, we applied this scoring model to the DNA-methylation data of the VP- and UV-MCC cell lines, revealing that both clearly scored as epithelial cancers. In summary, our comprehensive analysis of DNA-methylation suggests a common epithelial origin of UV- and VP-MCC cell lines.

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Distinct transcriptional programs of SOX2 in different types of small cell lung cancers

Cited by 13 publications

References 43 publications

Integrated Immunohistochemical Study on Small-Cell Carcinoma of the Lung Focusing on Transcription and Co-Transcription Factors

Integrated Immunohistochemical Study on Small-Cell Carcinoma of the Lung Focusing on Transcription and Co-Transcription Factors

Transcriptome Dynamics of Human Neuronal Differentiation From iPSC

DNA-methylation patterns imply a common cellular origin of virus- and UV-associated Merkel cell carcinoma

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