This study demonstrates that protein-coding RNA transcripts can regulate each other by competing for common microRNAs, a phenomenon termed competing endogenous RNAs (ceRNAs). The research focuses on the tumor suppressor PTEN, whose levels are critical for tumor suppression. By combining computational and experimental approaches, the study identifies and validates endogenous protein-coding transcripts that regulate PTEN, antagonize the PI3K/AKT signaling pathway, and exhibit growth and tumor suppressive properties. These transcripts show concordant expression patterns with PTEN and copy number loss in cancers, suggesting a previously unrecognized RNA-dependent tumor suppressive function. The study proposes a method to predict and validate ceRNA activity and networks, highlighting the trans-regulatory function of protein-coding mRNAs. The research identifies 158 candidate protein-coding transcripts as potential trans-regulators of PTEN, with several showing significant co-expression with PTEN in human cancers. These ceRNAs modulate PTEN levels, and their regulation is dependent on microRNA binding. The study further demonstrates that ceRNA-mediated regulation of PTEN activates the PI3K/AKT pathway, promoting tumor growth. Additionally, the study shows that ceRNAs such as CNOT6L and VAPA possess tumor suppressive properties, as evidenced by their reduced expression in cancer specimens and their role in tumor suppression in mouse models. The findings suggest that ceRNAs can function as a regulatory network, enabling RNA molecules to communicate and exert their functions through a non-coding language. This study provides a framework for identifying and validating ceRNAs, expanding the understanding of RNA-based regulatory mechanisms in cancer biology. The results highlight the importance of ceRNA interactions in tumor suppression and the potential for developing new therapeutic strategies targeting these regulatory networks.This study demonstrates that protein-coding RNA transcripts can regulate each other by competing for common microRNAs, a phenomenon termed competing endogenous RNAs (ceRNAs). The research focuses on the tumor suppressor PTEN, whose levels are critical for tumor suppression. By combining computational and experimental approaches, the study identifies and validates endogenous protein-coding transcripts that regulate PTEN, antagonize the PI3K/AKT signaling pathway, and exhibit growth and tumor suppressive properties. These transcripts show concordant expression patterns with PTEN and copy number loss in cancers, suggesting a previously unrecognized RNA-dependent tumor suppressive function. The study proposes a method to predict and validate ceRNA activity and networks, highlighting the trans-regulatory function of protein-coding mRNAs. The research identifies 158 candidate protein-coding transcripts as potential trans-regulators of PTEN, with several showing significant co-expression with PTEN in human cancers. These ceRNAs modulate PTEN levels, and their regulation is dependent on microRNA binding. The study further demonstrates that ceRNA-mediated regulation of PTEN activates the PI3K/AKT pathway, promoting tumor growth. Additionally, the study shows that ceRNAs such as CNOT6L and VAPA possess tumor suppressive properties, as evidenced by their reduced expression in cancer specimens and their role in tumor suppression in mouse models. The findings suggest that ceRNAs can function as a regulatory network, enabling RNA molecules to communicate and exert their functions through a non-coding language. This study provides a framework for identifying and validating ceRNAs, expanding the understanding of RNA-based regulatory mechanisms in cancer biology. The results highlight the importance of ceRNA interactions in tumor suppression and the potential for developing new therapeutic strategies targeting these regulatory networks.