This study demonstrates that protein-coding RNA transcripts can interact by competing for common microRNAs, a phenomenon termed competing endogenous RNAs (ceRNAs). The authors focused on PTEN, a key tumor suppressor, and identified and validated endogenous protein-coding transcripts that regulate PTEN, antagonize PI3K/AKT signaling, and exhibit growth and tumor suppressive properties. Notably, these genes show concordant expression patterns with PTEN and copy number loss in cancers. The study presents a roadmap for predicting and validating ceRNA activity and networks, highlighting the trans-regulatory function of protein-coding mRNAs. The findings expand the functional genetic information in the genome and provide a new mechanism for RNA communication and regulation.This study demonstrates that protein-coding RNA transcripts can interact by competing for common microRNAs, a phenomenon termed competing endogenous RNAs (ceRNAs). The authors focused on PTEN, a key tumor suppressor, and identified and validated endogenous protein-coding transcripts that regulate PTEN, antagonize PI3K/AKT signaling, and exhibit growth and tumor suppressive properties. Notably, these genes show concordant expression patterns with PTEN and copy number loss in cancers. The study presents a roadmap for predicting and validating ceRNA activity and networks, highlighting the trans-regulatory function of protein-coding mRNAs. The findings expand the functional genetic information in the genome and provide a new mechanism for RNA communication and regulation.