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Genomic Landscape Survey Identifies SRSF1 as a Key Oncodriver in Small Cell Lung Cancer.

Jiang L, Huang J, Higgs BW, Hu Z, Xiao Z, Yao X, Conley S, Zhong H, Liu Z, Brohawn P, Shen D, Wu S, Ge X, Jiang Y, Zhao Y, Lou Y, Morehouse C, Zhu W, Sebastian Y, Czapiga M, Oganesyan V, Fu H, Niu Y, Zhang W, Streicher K, Tice D, Zhao H, Zhu M, Xu L, Herbst R, Su X, Gu Y, Li S, Huang L, Gu J, Han B, Jallal B, Shen H, Yao Y - PLoS Genet. (2016)

Bottom Line: A few sequencing studies performed on limited number of samples have revealed potential disease-driving genes in SCLC, however, much still remains unknown, particularly in the Asian patient population.Here we conducted whole exome sequencing (WES) and transcriptomic sequencing of primary tumors from 99 Chinese SCLC patients.Additionally, Serine/Arginine Splicing Factor 1 (SRSF1) DNA copy number gain and mRNA over-expression was strongly associated with poor survival using both discovery and validation patient cohorts.

View Article: PubMed Central - PubMed

Affiliation: Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

ABSTRACT
Small cell lung cancer (SCLC) is an aggressive disease with poor survival. A few sequencing studies performed on limited number of samples have revealed potential disease-driving genes in SCLC, however, much still remains unknown, particularly in the Asian patient population. Here we conducted whole exome sequencing (WES) and transcriptomic sequencing of primary tumors from 99 Chinese SCLC patients. Dysregulation of tumor suppressor genes TP53 and RB1 was observed in 82% and 62% of SCLC patients, respectively, and more than half of the SCLC patients (62%) harbored TP53 and RB1 mutation and/or copy number loss. Additionally, Serine/Arginine Splicing Factor 1 (SRSF1) DNA copy number gain and mRNA over-expression was strongly associated with poor survival using both discovery and validation patient cohorts. Functional studies in vitro and in vivo demonstrate that SRSF1 is important for tumorigenicity of SCLC and may play a key role in DNA repair and chemo-sensitivity. These results strongly support SRSF1 as a prognostic biomarker in SCLC and provide a rationale for personalized therapy in SCLC.

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Related in: MedlinePlus

Mechanism of action for SRSF1 in SCLC.a) SRSF1 prevents DNA-damage. DMS114 cells were transfected with control or SRSF1 siRNA and then treated with topotecan or Cisplatin for the indicated times. SRSF1, phosphor-H2AX and phosphor-Chk2 were probed with their corresponding antibodies. b) c) SRSF1 mediates the activation of AKT and ERK pathways. DMS114 cells transfected with ctrl or SRSF1 siRNAs were lysed and applied to the phospho-kinase array as detailed in Materials and Methods. The dot blot result was further confirmed by western blot in both DMS114 and NCI-H1048 cells.
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pgen.1005895.g005: Mechanism of action for SRSF1 in SCLC.a) SRSF1 prevents DNA-damage. DMS114 cells were transfected with control or SRSF1 siRNA and then treated with topotecan or Cisplatin for the indicated times. SRSF1, phosphor-H2AX and phosphor-Chk2 were probed with their corresponding antibodies. b) c) SRSF1 mediates the activation of AKT and ERK pathways. DMS114 cells transfected with ctrl or SRSF1 siRNAs were lysed and applied to the phospho-kinase array as detailed in Materials and Methods. The dot blot result was further confirmed by western blot in both DMS114 and NCI-H1048 cells.

Mentions: DNA-damage induction as a potential effect of SRSF1 knockdown based on our DNA-repair analysis was assessed. Inductions of p-H2AX and Chk2, established markers of DNA-strand breaks and DNA-repair response [23, 24], were consistently observed upon SRSF1 abrogation in DMS114 and SHP-77 (Fig 5A and S7B Fig), and increased phosphorylations were observed when we combined SRSF1 siRNA transfection and treatment with cisplatin or topotecan.


Genomic Landscape Survey Identifies SRSF1 as a Key Oncodriver in Small Cell Lung Cancer.

Jiang L, Huang J, Higgs BW, Hu Z, Xiao Z, Yao X, Conley S, Zhong H, Liu Z, Brohawn P, Shen D, Wu S, Ge X, Jiang Y, Zhao Y, Lou Y, Morehouse C, Zhu W, Sebastian Y, Czapiga M, Oganesyan V, Fu H, Niu Y, Zhang W, Streicher K, Tice D, Zhao H, Zhu M, Xu L, Herbst R, Su X, Gu Y, Li S, Huang L, Gu J, Han B, Jallal B, Shen H, Yao Y - PLoS Genet. (2016)

Mechanism of action for SRSF1 in SCLC.a) SRSF1 prevents DNA-damage. DMS114 cells were transfected with control or SRSF1 siRNA and then treated with topotecan or Cisplatin for the indicated times. SRSF1, phosphor-H2AX and phosphor-Chk2 were probed with their corresponding antibodies. b) c) SRSF1 mediates the activation of AKT and ERK pathways. DMS114 cells transfected with ctrl or SRSF1 siRNAs were lysed and applied to the phospho-kinase array as detailed in Materials and Methods. The dot blot result was further confirmed by western blot in both DMS114 and NCI-H1048 cells.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4836692&req=5

pgen.1005895.g005: Mechanism of action for SRSF1 in SCLC.a) SRSF1 prevents DNA-damage. DMS114 cells were transfected with control or SRSF1 siRNA and then treated with topotecan or Cisplatin for the indicated times. SRSF1, phosphor-H2AX and phosphor-Chk2 were probed with their corresponding antibodies. b) c) SRSF1 mediates the activation of AKT and ERK pathways. DMS114 cells transfected with ctrl or SRSF1 siRNAs were lysed and applied to the phospho-kinase array as detailed in Materials and Methods. The dot blot result was further confirmed by western blot in both DMS114 and NCI-H1048 cells.
Mentions: DNA-damage induction as a potential effect of SRSF1 knockdown based on our DNA-repair analysis was assessed. Inductions of p-H2AX and Chk2, established markers of DNA-strand breaks and DNA-repair response [23, 24], were consistently observed upon SRSF1 abrogation in DMS114 and SHP-77 (Fig 5A and S7B Fig), and increased phosphorylations were observed when we combined SRSF1 siRNA transfection and treatment with cisplatin or topotecan.

Bottom Line: A few sequencing studies performed on limited number of samples have revealed potential disease-driving genes in SCLC, however, much still remains unknown, particularly in the Asian patient population.Here we conducted whole exome sequencing (WES) and transcriptomic sequencing of primary tumors from 99 Chinese SCLC patients.Additionally, Serine/Arginine Splicing Factor 1 (SRSF1) DNA copy number gain and mRNA over-expression was strongly associated with poor survival using both discovery and validation patient cohorts.

View Article: PubMed Central - PubMed

Affiliation: Department of Pulmonary, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

ABSTRACT
Small cell lung cancer (SCLC) is an aggressive disease with poor survival. A few sequencing studies performed on limited number of samples have revealed potential disease-driving genes in SCLC, however, much still remains unknown, particularly in the Asian patient population. Here we conducted whole exome sequencing (WES) and transcriptomic sequencing of primary tumors from 99 Chinese SCLC patients. Dysregulation of tumor suppressor genes TP53 and RB1 was observed in 82% and 62% of SCLC patients, respectively, and more than half of the SCLC patients (62%) harbored TP53 and RB1 mutation and/or copy number loss. Additionally, Serine/Arginine Splicing Factor 1 (SRSF1) DNA copy number gain and mRNA over-expression was strongly associated with poor survival using both discovery and validation patient cohorts. Functional studies in vitro and in vivo demonstrate that SRSF1 is important for tumorigenicity of SCLC and may play a key role in DNA repair and chemo-sensitivity. These results strongly support SRSF1 as a prognostic biomarker in SCLC and provide a rationale for personalized therapy in SCLC.

Show MeSH
Related in: MedlinePlus