HMGA2 promotes intestinal tumorigenesis by facilitating MDM2-mediated ubiquitination and degradation of p53.

High mobility group A2 (HMGA2) is an architectural transcription factor that promotes human colorectal cancer (CRC) aggressiveness by modulating the transcription of target genes. The degradation of p53 is mediated by murine double minute 2 (MDM2) in a proteasome-dependent manner. Here we report that HMGA2 promotes cell cycle progression and inhibits apoptosis in CRC cells in vitro. We also developed an intestinal epithelial cell-specific Hmga2 knock-in (KI) mouse model. It revealed that the Hmga2 KI promoted chemical carcinogen-induced tumorigenesis in the intestine in vivo. In studying the underlying molecular mechanism, we found that HMGA2 formed a protein complex with p53. The tetramerization domain of p53 (amino acids 294-393) and the three AT-hook domains (amino acids 1-83) of HMGA2 were responsible for their direct interaction. We also found that HMGA2 directly bound to MDM2 and the central acidic and zinc finger domains of MDM2 (amino acids 111-360) were required for interaction with HMGA2. Furthermore, our results indicated that HMGA2 promoted MDM2-mediated p53 ubiquitination and degradation. Interestingly, Hmga2 overexpression in Hmga2 KI mice resulted in an increase in the accumulation of ubiquitinated p53. In addition, in two large CRC cohorts, it was demonstrated that high HMGA2 expression was predictive of an adverse outcome in the p53-negative subgroup of CRC patients. In summary, our data have established for the first time a novel mechanism by which HMGA2 functions with p53 and MDM2 to promote CRC progression. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Circulating cell-free high mobility group AT-hook 2 mRNA as a detection marker in the serum of colorectal cancer patients.

BACKGROUND: Detection of circulating cell-free mRNA serves as noninvasive tools for cancer diagnosis. As an oncofetal protein, HMGA2 (high mobility group AT-hook 2) is upregulated in colorectal cancer (CRC) tissues. However, it is not clear whether the increased levels of circulating cell-free HMGA2 mRNA functions as potential biomarkers for improved diagnosis of CRC. METHODS: To assess its clinical significance in diagnosis and prediction, we evaluated serum levels of circulating HMGA2 mRNA in CRC patients and in healthy controls. In this study, 83 CRC patients and 11 normal controls were enrolled in this study. We used real-time quantitative reverse transcription-PCR to evaluate the plasma mRNA levels of HMGA2 and analyze the correlation between their expression and clinicopathologic characteristics. RESULTS: We found that the levels of HMGA2 mRNA were significantly higher in CRC patients compared with healthy volunteers. The patients with right-sided CRC, colon cancer, positive nerve infiltration, positive vascular invasion, negative microsatellite instability (MSI), and increasing in serum carbohydrate antigen (CA) 199 had higher levels of plasma HMGA2 mRNA. A strong positive correlation between circulating cell-free HMGA2 mRNA and CA199 level in serum was found in our study. Furthermore, statistical analysis revealed that levels of HMGA2 mRNA in plasma and in tumors were strictly correlated. CONCLUSIONS: Collectively, our data suggested that cell-free HMGA2 mRNA in plasma might function as a novel diagnostic marker for CRC.

Transcriptional activation of FN1 and IL11 by HMGA2 promotes the malignant behavior of colorectal cancer.

Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide, and metastasis is the principle reason for its poor prognosis. Overexpression of high-mobility gene group A2 (HMGA2) contributes to the aggressiveness of CRC. However, the underlying molecular mechanism of its overexpression is still elusive. In this study, we showed that ectopic expression of HMGA2 significantly enhanced cell migration and invasion in vitro and promoted tumor growth and distant metastasis in vivo In contrast, the silencing of HMGA2 produced the opposite effects in vitro and in vivo Chromatin immunoprecipitation-PCR and luciferase assays revealed that HMGA2 bound directly to the promoters of FN1 and IL11 and significantly induced their transcriptional activities. Moreover, as the direct downstream target of HMGA2, IL11 modulated cell migration and invasion through a pSTAT3-dependent signaling pathway. Furthermore, a strong positive correlation between HMGA2 and IL11 expression was identified in 122 CRC tissues. High IL11 expression was associated with poor differentiation, a large tumor size, lymph node metastasis and low overall survival in CRC patients. Collectively, our data reveal novel insights into the molecular mechanisms underlying HMGA2-mediated CRC metastasis and highlight the possibility of targeting HMGA2 and IL11 for treating CRC patients with metastasis.

Gene expression analyses identify a relationship between stanniocalcin 2 and the malignant behavior of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the main causes of cancer-related death worldwide. Stanniocalcin 2 (STC2), a secreted glycoprotein, has been suggested to exert various functions in progression of many cancers. However, the precise biological role in CRC is not fully understood. Therefore, this study based on several public datasets aims at investigating the roles of STC2 in CRC. METHODS: We used The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to evaluate the STC2 expression and its clinical significance in CRC. Cell migration and invasion by STC2 overexpression and knockdown were assessed using Transwell migration and Matrigel invasion assays. We next performed RNAseq analysis on SW480 cells with or without STC2 overexpression. Differentially expressed genes were selected by using fold-change >5 and P-value <0.05. RESULTS: In this study, we found that STC2 level was significantly higher in CRC than that in adjacent noncancerous tissues from TCGA and GEO. Tumors with high mRNA levels of STC2 were more common in patients with rectal cancer, left-sided CRC, advanced T-stage (T3-T4), positive lymph node involvement and advanced AJCC-stage (III-IV) from TCGA. STC2 displayed the negative correlation with the expressions of epithelial cell markers, while it was positively correlated with the expressions of mesenchymal cell markers, MMPs and the epithelial-mesenchymal transition (EMT)-related transcriptional factors. Furthermore, we found that STC2 promoted cell migration and invasion in vitro. And a group of differentially expressed genes, which were modulated by STC2, were identified from RNAseq analyses. CONCLUSION: Our study demonstrates that STC2 is overexpressed in CRC compared with normal tissues, and promotes CRC cell migration and invasion. Our data suggest that STC2 may be used as a potential biomarker for clinical application and target therapy in future.