Abstract
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 G0/1 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.
Highlights
A major obstacle for cure of cancer is that we still do not sufficiently understand how a cancer is initiated and progressed, despite the revived cancer stem cell (CSC) hypothesis [1,2,3,4]
These results suggest that the gene products amplified by the primers Pmili may not necessarily represent full length Piwil2 transcripts and that ‘‘Piwil2’’ mRNAs detected by this primer pair in the precancerous stem cells (pCSCs) might represent a Piwil2 variant(s), likely truncated at the 59-end (Fig. 1D)
While exploring the mechanism underlying Piwil2-mediated tumor development, we found by GEM RT-PCR that the ‘‘Piwil2’’ transcripts expressed in the murine pCSCs were truncated at 59-end and absent of first 6 exons of Piwil2
Summary
A major obstacle for cure of cancer is that we still do not sufficiently understand how a cancer is initiated and progressed, despite the revived cancer stem cell (CSC) hypothesis [1,2,3,4]. The identification of pCSCs suggests that pCSCs are a precursor of CSCs [1] Both pCSCs and CSCs, which are considered to represent two developing stages of tumor stem cells (TSCs) [1,3,4], can serve as tumor vasculogenic progenitor cells (TVPCs) [6,7]. Through the study of pCSCs, we have found that the transcripts of germline stem cell (GSC) gene PIWIL2 are constantly expressed in pCSC lines, but not in normal bonemarrow (BM)-derived stem/progenitor cells [5], suggesting that it may play an important role in TSC development [1,3,4]
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