Identification of Piwil2-like (PL2L) proteins that promote tumorigenesis.
PIWIL2, a member of PIWI/AGO gene family, is expressed in the germline stem cells (GSCs) of testis for gametogenesis but not in adult somatic and stem cells. It has been implicated to play an important role in tumor development. We have previously reported that precancerous stem cells (pCSCs) constitutively express Piwil2 transcripts to promote their proliferation. Here we show that these transcripts de facto represent Piwil2-like (PL2L) proteins. We have identified several PL2L proteins including PL2L80, PL2L60, PL2L50 and PL2L40, using combined methods of Gene-Exon-Mapping Reverse Transcription Polymerase Chain Reaction (GEM RT-PCR), bioinformatics and a group of novel monoclonal antibodies. Among them, PL2L60 rather than Piwil2 and other PL2L proteins is predominantly expressed in various types of human and mouse tumor cells. It promotes tumor cell survival and proliferation in vitro through up-regulation of Stat3 and Bcl2 gene expressions, the cell cycle entry from G(0/1) into S-phase, and the nuclear expression of NF-κB, which contribute to the tumorigenicity of tumor cells in vivo. Consistently, PL2L proteins rather than Piwil2 are predominantly expressed in the cytoplasm or cytoplasm and nucleus of euchromatin-enriched tumor cells in human primary and metastatic cancers, such as breast and cervical cancers. Moreover, nuclear PL2L proteins are always co-expressed with nuclear NF-κB. These results reveal that PL2L60 can coordinate with NF-κB to promote tumorigenesis and might mediate a common pathway for tumor development without tissue restriction. The identification of PL2L proteins provides a novel insight into the mechanisms of cancer development as well as a novel bridge linking cancer diagnostics and anticancer drug development.
Department of Pathology, Ohio State University Medical Center, Columbus, Ohio, United States of America.
Yin
Y
Ye
De-Tao
DT
Yin
Li
L
Chen
Quansheng
Q
Zhou
Rulong
R
Shen
Gang
G
He
Qingtao
Q
Yan
Zhenyu
Z
Tong
Andrew C
AC
Issekutz
Charles L
CL
Shapiro
Sanford H
SH
Barsky
Haifan
H
Lin
Jian-Jian
JJ
Li
Jian-Xin
JX
Gao
D000818:Animals; D060565:Argonaute Proteins; D001483:Base Sequence; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D017931:DNA Primers; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000502:physiology
D060565:Argonaute Proteins; D017931:DNA Primers; D016328:NF-kappa B; C486868:PIWIL2 protein, human; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor