PMID- 30793164
OWN - NLM
STAT- MEDLINE
DCOM- 20200527
LR  - 20200527
IS  - 1460-2180 (Electronic)
IS  - 0143-3334 (Linking)
VI  - 40
IP  - 10
DP  - 2019 Oct 16
TI  - DIAPH2 alterations increase cellular motility and may contribute to the 
      metastatic potential of laryngeal squamous cell carcinoma.
PG  - 1251-1259
LID - 10.1093/carcin/bgz035 [doi]
AB  - Low 5-year survival rate in laryngeal squamous cell carcinoma (LSCC) is to large 
      extent attributable to high rate of recurrences and metastases. Despite the 
      importance of the latter process, its complex genetic background remains not 
      fully understood. Recently, we identified two metastasis-related candidate genes, 
      DIAPH2 and DIAPH3 to be frequently targeted by hemizygous/homozygous deletions, 
      respectively, in LSCC cell lines. They physiologically regulate such processes as 
      cell movement and adhesion, hence we found it as a rationale, to study if tumor 
      LSCC specimens harbor mutations of these genes and whether the mutations are 
      associated with metastasizing tumors. As a proof of concept, we sequenced both 
      genes in five LSCC cell lines derived from lymph node metastases assuming there 
      the highest probability of finding alterations. Indeed, we identified one 
      hemizygous deletion (c.3116_3240del125) in DIAPH2 targeting the FH2 domain. 
      Moreover, we analyzed 95 LSCC tumors (53 N0 and 42 N+) using the Illumina 
      platform and identified three heterozygous single nucleotide variants in DIAPH2 
      targeting conserved domains exclusively in N+ tumors. By combining these results 
      with cBioPortal data we showed significant enrichment of DIAPH2 mutations (P = 
      0.036) in N+ tumors. To demonstrate the consequences of DIAPH2 inactivation, 
      CRISPR/Cas9 editing was used to obtain a heterozygous DIAPH2+/- mutant HEK-293T 
      cell line. Importantly, the edited line shows a shift from 'proliferation' to 
      'migration' phenotype typically observed in metastasizing cells. In conclusion, 
      we report that DIAPH2 alterations are present primarily in metastasizing 
      specimens of LSCC and suggest that they may contribute to the metastatic 
      potential of the tumor.
CI  - (c) The Author(s) 2019. Published by Oxford University Press. All rights reserved. 
      For Permissions, please email: journals.permissions@oup.com.
FAU - Kostrzewska-Poczekaj, M
AU  - Kostrzewska-Poczekaj M
AD  - Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
FAU - Byzia, E
AU  - Byzia E
AD  - Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
FAU - Soloch, N
AU  - Soloch N
AD  - Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
FAU - Jarmuz-Szymczak, M
AU  - Jarmuz-Szymczak M
AD  - Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
AD  - Department of Hematology and Bone Marrow Transplantation, Poznan University of 
      Medical Sciences, Poznan, Poland.
FAU - Janiszewska, J
AU  - Janiszewska J
AD  - Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
FAU - Kowal, E
AU  - Kowal E
AD  - Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
FAU - Paczkowska, J
AU  - Paczkowska J
AD  - Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
FAU - Kiwerska, K
AU  - Kiwerska K
AD  - Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
AD  - Department of Tumor Pathology, Greater Poland Cancer Center, Poznan, Poland.
FAU - Wierzbicka, M
AU  - Wierzbicka M
AD  - Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
AD  - Department of Otolaryngology and Laryngological Oncology, Poznan University of 
      Medical Sciences, Poznan, Poland.
FAU - Bartochowska, A
AU  - Bartochowska A
AD  - Department of Otolaryngology and Laryngological Oncology, Poznan University of 
      Medical Sciences, Poznan, Poland.
FAU - Ustaszewski, A
AU  - Ustaszewski A
AD  - Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
FAU - Greczka, G
AU  - Greczka G
AD  - Department of Otolaryngology and Laryngological Oncology, Poznan University of 
      Medical Sciences, Poznan, Poland.
FAU - Grenman, R
AU  - Grenman R
AD  - Department of Otorhinolaryngology-Head and Neck Surgery, Turku University Central 
      Hospital and Turku University, Turku, Finland.
FAU - Szyfter, K
AU  - Szyfter K
AD  - Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
FAU - Giefing, M
AU  - Giefing M
AD  - Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
AD  - Department of Otolaryngology and Laryngological Oncology, Poznan University of 
      Medical Sciences, Poznan, Poland.
LA  - eng
PT  - Journal Article
PL  - England
TA  - Carcinogenesis
JT  - Carcinogenesis
JID - 8008055
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (DIAPH2 protein, human)
RN  - 0 (Formins)
SB  - IM
MH  - Apoptosis
MH  - Biomarkers, Tumor/genetics/*metabolism
MH  - Carcinoma, Squamous Cell/genetics/metabolism/*secondary
MH  - Case-Control Studies
MH  - *Cell Movement
MH  - Cell Proliferation
MH  - Follow-Up Studies
MH  - Formins/genetics/*metabolism
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Laryngeal Neoplasms/genetics/metabolism/*pathology
MH  - Lymphatic Metastasis
MH  - Prognosis
MH  - Survival Rate
MH  - Tumor Cells, Cultured
EDAT- 2019/02/23 06:00
MHDA- 2020/05/28 06:00
CRDT- 2019/02/23 06:00
PHST- 2018/11/05 00:00 [received]
PHST- 2019/01/30 00:00 [revised]
PHST- 2019/02/20 00:00 [accepted]
PHST- 2019/02/23 06:00 [pubmed]
PHST- 2020/05/28 06:00 [medline]
PHST- 2019/02/23 06:00 [entrez]
AID - 5359425 [pii]
AID - 10.1093/carcin/bgz035 [doi]
PST - ppublish
SO  - Carcinogenesis. 2019 Oct 16;40(10):1251-1259. doi: 10.1093/carcin/bgz035.