PBX3 Is Part of an EMT Regulatory Network and Indicates Poor Outcome in Colorectal Cancer

Abstract

Colorectal cancers are composed of phenotypically different tumor cell subpopulations within the same core genetic background. Here, we identify high expression of the TALE transcription factor PBX3 in tumor cells undergoing epithelial-mesenchymal transition (EMT), analyze PBX3 regulation, and determine clinical associations in colorectal cancer. We used transcriptomic and analyses to identify PBX3 expression in colorectal cancer and cell biology approaches to determine its regulation and function. Clinical associations were analyzed in independent tissue collections and gene expression datasets of colorectal cancers with recorded follow-up data. PBX3 was expressed in tumor cells with high WNT activity undergoing EMT at the leading tumor edge of colorectal cancers, whereas stromal cells were PBX3 negative. PBX3 expression was induced by WNT activation and by the EMT transcription factors SNAIL and ZEB1, whereas these effects were mediated indirectly through microRNA miR-200. PBX3 was required for a full EMT phenotype in colon cancer cells. On the protein level, PBX3 expression indicated poor cancer-specific and disease-free survival in a cohort of 244 UICC stage II colorectal cancers, and was associated with metastasis in a case-control collection consisting of 90 cases with or without distant metastasis. On the mRNA level, high PBX3 expression was strongly linked to poor disease-free survival. PBX3 is a novel indicator of EMT in colorectal cancer, part of an EMT regulatory network, and a promising prognostic predictor that may aid in therapeutic decision making for patients with colorectal cancer. .

SNAIL1 employs β‐Catenin‐LEF1 complexes to control colorectal cancer cell invasion and proliferation

“…Thus, additional transcription factors and signalling pathways must exist whose activation and repression contributes to the aggregated gene expression changes in the course of EMT. FOXA and SMAD proteins, AP4, and PBX3 are transcription factors with roles in EMT suppression and execution . Therefore, the conversion of epithelial into mesenchymal gene expression likely follows a gradual and hierarchical pattern whereby core EMT TFs trigger sequential changes in the activity of an expanding number of signalling pathways and TFs .…”

PBX3 hypermethylation in peripheral blood leukocytes predicts better prognosis in colorectal cancer: A propensity score analysis

“…Furthermore, in the subgroup analyses of CRC prognosis, we found that PBX3 hypermethylation was associated with better 10‐years OS in the male, normal weight, colon, and UICC stage III subgroups (Figure ). At present, a research result shows that PBX3 was required for the complete EMT phenotype in colon cancer cells . But the reasons for these phenomena in PBLs were still unclear and need to be validated in future studies.…”

“…Recent mechanism researches indicated that PBX3 expressed in tumor cells with high WNT activity undergoing EMT as a new indicator that is associated with poor prognosis in CRC and PBX3 mRNA expression was also highly significantly associated with poor outcome . Other research found that let‐7c serves as a tumor metastasis suppressor by inhibiting PBX3 mRNA expression .…”

“…At present, a research result shows that PBX3 was required for the complete EMT phenotype in colon cancer cells. 45 But the reasons for these phenomena in PBLs were still unclear and need to be validated in future studies.…”

“…It is worth noting that in CRC, PBX3 has been associated with tumor progression and metastasis. Recent research reported that PBX3 is a novel indicator of epithelial‐mesenchymal transition (EMT) in CRC, and a promising prognostic predictor that may aid in therapeutic decision‐making for patients with CRC . These data suggested oncogenic features of PBX3 in CRC, but no previous study had evaluated whether PBX3 methylation in PBL, as a noninvasive test, is a biomarker in CRC to predict prognosis.…”