HMGA1 silencing restores normal stem cell characteristics in colon cancer stem cells by increasing p53 levels

Puca, Francomichele; Colamaio, Marianna; Federico, Antonella; Gemei, Marica; Tosti, Nadia; Bastos, André Uchimura; Vecchio, Luigi Del; Pece, Salvatore; Battista, Sabrina

doi:10.18632/oncotarget.1914

Cited by 65 publications

(62 citation statements)

References 34 publications

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“…For overexpression, the pCDNA3.1-HMGA1 and the empty control vectors were constructed as previously described [10]. For down-regulation, the hairpin RNA interference plasmid for human HMGA1 (pLKO.1-HMGA1, TRCN0000018949) and the scramble control pLKO.1-Puro plasmid (SHC002) were purchased from Sigma-Aldrich (Sigma-Aldrich, St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

“…Of its many roles, HMGA1 negatively regulates TP53 [10] and promotes an undifferentiated pluripotent stem-like cell state through the induction of SOX2 , LIN28 and cMYC [11]. HMGA1 also directly activates genes involved in tumor growth, migration, invasion, resistance to drug-induced cell death and epithelial-mesenchymal transition in cancer cells [12], [13], [14], [15].…”

Section: Introductionmentioning

confidence: 99%

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HMGA1 Expression in Human Hepatocellular Carcinoma Correlates with Poor Prognosis and Promotes Tumor Growth and Migration in in vitro Models

et al. 2016

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BACKGROUND: HMGA1 is a non-histone nuclear protein that regulates cellular proliferation, invasion and apoptosis and is overexpressed in many carcinomas. In this study we sought to explore the expression of HMGA1 in HCCs and cirrhotic tissues, and its effect in in vitro models. METHODS: We evaluated HMGA1 expression using gene expression microarrays (59 HCCs, of which 37 were matched with their corresponding cirrhotic tissue and 5 normal liver donors) and tissue microarray (192 HCCs, 108 cirrhotic tissues and 79 normal liver samples). HMGA1 expression was correlated with clinicopathologic features and patient outcome. Four liver cancer cell lines with stable induced or knockdown expression of HMGA1 were characterized using in vitro assays, including proliferation, migration and anchorage-independent growth. RESULTS: HMGA1 expression increased monotonically from normal liver tissues to cirrhotic tissue to HCC (P < .01) and was associated with Edmondson grade (P < .01). Overall, 51% and 42% of HCCs and cirrhotic tissues expressed HMGA1, respectively. Patients with HMGA1-positive HCCs had earlier disease progression and worse overall survival. Forced expression of HMGA1 in liver cancer models resulted in increased cell growth and migration, and vice versa. Soft agar assay showed that forced expression of HMGA1 led to increased foci formation, suggesting an oncogenic role of HMGA1 in hepatocarcinogenesis. CONCLUSIONS: HMGA1 is frequently expressed in cirrhotic tissues and HCCs and its expression is associated with high Edmondson grade and worse prognosis in HCC. Our results suggest that HMGA1 may act as oncogenic driver of progression, implicating it in tumor growth and migration potential in liver carcinogenesis.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HMGA1 Expression in Human Hepatocellular Carcinoma Correlates with Poor Prognosis and Promotes Tumor Growth and Migration in in vitro Models

et al. 2016

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“…Although several studies have indicated that p53 may be involved in the regulation of colon cancer stem cells (33,34), the precise mechanisms are relatively unclear. The present study demonstrated that wild-type p53 transactivated the promoter of the CD133 gene, indicating that the CD133 gene may be a novel target of p53 in colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

p53 positively regulates the expression of cancer stem cell marker CD133 in HCT116 colon cancer cells

et al. 2018

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Abstract. Colon cancer stem cells (CSCs), which are highly capable of self-renewal and proliferation, are involved in colon tumorigenesis and response to therapy. CD133 is considered the most robust surface marker for colorectal cancer stem cells. Although the TP53 gene is frequently mutated in colon cancer, it remains not fully understood whether and how tumor protein p53 (p53) is associated with CD133 expression in colon cancer cells. In the present study, the expression of the CSC biomarker CD133 was investigated in terms of p53 status in colorectal carcinoma HCT116 cells. p53 wild-type HCT116 (HCT116 p53 IntroductionColorectal carcinoma (CRC), which is prone to metastasis and recurrence, is a cancer with a high lethality rate worldwide. More than 50% of patients will develop metastasis and recurrence (1,2). Multiple factors account for metastasis and recurrence, including tumor stage, cancer subtypes and cancer stem cells (CSCs). CSCs are a small population of tumor-initiating cells that have the ability to self-renew and differentiate in tumors in vivo. CSCs are involved in various processes during tumor formation, progression, and angiogenesis and are considered an important target for novel cancer treatment strategies (3). Several specific surface markers are expressed on CSCs, including CD133, CD44 and aldehyde dehydrogenase 1 (ALDH1) (4). CD133 (also known as prominin-1) is a 5-transmembrane glycoprotein of 865 amino acids with a total molecular weight of 120 kDa. CD133 is a CSC marker in colon carcinoma. CD133-positive cells correlate strongly with poor prognosis and synchronous liver metastasis (5). Cancer cell populations with high expression of CD133 are much more aggressive in terms of metastases compared with those with low expression of CD133, suggesting that CD133 may be a marker of increased tumorigenesis ability. CD133-positive cells from clinical biopsy-derived cultures have been demonstrated to possess multilineage differentiation potential and are capable of tumor initiation in vivo. CD133-positive CRC cells are more resistant to chemoradiotherapy, and CD133 expression is associated with poor prognosis (6,7). However, the regulation of CD133 expression has not been fully elucidated.The present study demonstrated that CD133 expression was associated with the tumor protein p53 (p53) expression in an HCT116 p53 +/+ cell line. Of note, CD133-negative cells were detected in the colon cancer cell line HCT116 in a previous report by Kai et al (8

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“…Their overexpression is associated with a highly malignant phenotype and correlates with the presence of metastasis and reduced survival [8, 9]. Several studies implicate the expression of the HMGA genes in the process of carcinogenesis [10-18]. However, although HMGA overexpression is known to play a critical role in malignant cell transformation, the mechanisms regulating HMGA protein levels remain largely obscure.…”

Section: Introductionmentioning

confidence: 99%

HMGA1pseudogenes as candidate proto-oncogenic competitive endogenous RNAs

et al. 2014

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The High Mobility Group A (HMGA) are nuclear proteins that participate in the organization of nucleoprotein complexes involved in chromatin structure, replication and gene transcription. HMGA overexpression is a feature of human cancer and plays a causal role in cell transformation. Since non-coding RNAs and pseudogenes are now recognized to be important in physiology and disease, we investigated HMGA1 pseudogenes in cancer settings using bioinformatics analysis. Here we report the identification and characterization of two HMGA1 non-coding pseudogenes, HMGA1P6 and HMGA1P7. We show that their overexpression increases the levels of HMGA1 and other cancer-related proteins by inhibiting the suppression of their synthesis mediated by microRNAs. Consistently, embryonic fibroblasts from HMGA1P7-overexpressing transgenic mice displayed a higher growth rate and reduced susceptibility to senescence. Moreover, HMGA1P6 and HMGA1P7 were overexpressed in human anaplastic thyroid carcinomas, which are highly aggressive, but not in differentiated papillary carcinomas, which are less aggressive. Lastly, the expression of the HMGA1 pseudogenes was significantly correlated with HMGA1 protein levels thereby implicating HMGA1P overexpression in cancer progression. In conclusion, HMGA1P6 and HMGA1P7 are potential proto-oncogenic competitive endogenous RNAs.

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HMGA1 silencing restores normal stem cell characteristics in colon cancer stem cells by increasing p53 levels

Cited by 65 publications

References 34 publications

HMGA1 Expression in Human Hepatocellular Carcinoma Correlates with Poor Prognosis and Promotes Tumor Growth and Migration in in vitro Models

HMGA1 Expression in Human Hepatocellular Carcinoma Correlates with Poor Prognosis and Promotes Tumor Growth and Migration in in vitro Models

p53 positively regulates the expression of cancer stem cell marker CD133 in HCT116 colon cancer cells

HMGA1pseudogenes as candidate proto-oncogenic competitive endogenous RNAs

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