TBX1 functions as a tumor suppressor in colorectal cancer by PPP2R2B-mediated the inhibition of MAPK/ERK and PI3K/AKT signaling pathways

Abstract

Background: TBX1 is member of T-box family which is characterized by a 180–200 amino acid conserved DNA binding domain, and encodes important developmentally transcription factor. Deregulated TBX1 expression has been implicated in parathyroid tumors and inhibited tumorigenesis. However, its role in colorectal cancer has not been elucidated. Methods: In vitro functional studies were performed to assess the TBX1 of the proliferation and colony formation of colorectal cancer cells. Meanwhile, subcutaneous xenograft mouse model was established to determine the effect of TBX1 on tumor growth in vivo. The underlying mechanism of TBX1 in colorectal cancer cells was clarified by a series of molecular and biochemical experiments. Results: Our results showed that TBX1 was significantly down-regulated in colorectal cancers compared with control subjects, and demonstrated that ectopic expression of TBX1 in colorectal cancer cells strongly suppressed cell proliferation, colony-forming ability, cell migration, cell invasion and tumor growth in nude mice by the inhibition of MAPK/ERK and PI3K/AKT signaling pathways. Further studies revealed that TBX1 suppressed these two pathways by directly transcriptionally upregulating protein phosphatase 2 regulatory subunit B (PPP2R2B), thereby playing its tumor suppressor functions. As expected, PPP2R2B knockdown obviously attenuated the inhibitory effect of TBX1 on cell proliferation and colony formation as well as the activities of MAPK/ERK and PI3K/AKT pathways. Conclusion: The present study demonstrates that TBX1 acts as a putative tumor suppressor in colorectal cancer cells by inhibiting PPP2R2B-mediated MAPK/ERK and PI3K/AKT signaling pathways.