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Wnt/β-catenin activation cooperates with loss of p53 to cause adrenocortical carcinoma in mice.

ABSTRACT: Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited therapeutic options. The lack of mouse models that recapitulate the genetics of ACC has hampered progress in the field. We analyzed The Cancer Genome Atlas (TCGA) dataset for ACC and found that patients harboring alterations in both p53/Rb and Wnt/β-catenin signaling pathways show a worse prognosis compared with patients that harbored alterations in only one. To model this, we utilized the Cyp11b2(AS)^Cre mouse line to generate mice with adrenocortical-specific Wnt/β-catenin activation, Trp53 deletion, or the combination of both. Mice with targeted Wnt/β-catenin activation or Trp53 deletion showed no changes associated with tumor formation. In contrast, alterations in both pathways led to ACC with pulmonary metastases. Similar to ACCs in humans, these tumors produced increased levels of corticosterone and aldosterone and showed a high proliferation index. Gene expression analysis revealed that mouse tumors exhibited downregulation of Star and Cyp11b1 and upregulation of Ezh2, similar to ACC patients with a poor prognosis. Altogether, these data show that altering both Wnt/β-catenin and p53/Rb signaling is sufficient to drive ACC in mouse. This autochthonous model of ACC represents a new tool to investigate the biology of ACC and to identify new treatment strategies.

SUBMITTER: Borges KS

PROVIDER: S-EPMC7378041 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Glioblastoma multiforme (GBM) is the most prevalent type of adult brain tumor, and one of the deadliest tumors known to mankind. The genetic understanding of GBM is, however, limited, and the molecular mechanisms which facilitate GBM cell survival and growth within the tumor microenvironment are largely unknown. We applied digital karyotyping and single nucleotide polymorphism (SNP) arrays to screen for copy number changes in GBM samples and found that the most frequently amplified region is at chromosome 7p11.2. The high resolution of digital karyotyping and SNP arrays permits the precise delineation of amplicon boundaries and has enabled identification of the minimal region of amplification at 7p11.2, which contains two genes, EGFR and SEC61γ. SEC61γ encodes a subunit of a heterotrimeric protein channel located in the endoplasmic reticulum (ER). In addition to its high frequency of gene amplification in GBMs, SEC61γ is also remarkably overexpressed in 77% of GBMs, but not in lower-grade gliomas. The siRNA-mediated knockdown of SEC61γ expression in tumor cells led to growth suppression and apoptosis. Furthermore, we showed that pharmacological ER stress agents induce SEC61γ expression in GBM cells. Together, these results indicate that aberrant expression of SEC61γ serves significant roles in GBM cell survival, likely via a mechanism that is involved in the cytoprotective ER stress-adaptive response to the tumor microenvironment. hSETD1A was silenced in HCT116 cells using retrovirus harboring shRNA specifically against the hSETD1A gene. 10μg RNA was reverse transcribed to cDNA using the Applied Biosystems High Capacity cDNA Reverse Transcription kit according to the manufacturer’s instructions (Applied Biosystems). cDNA products were treated with 100ng RNaseA and then purified using the Qiagen PCR purification kit according to the manufacturer’s instructions. NimbleGen Human Gene Expression array was purchased from Roche Applied Sciences. cDNA samples were labeled, Cy3 hybridized, and processed at the FSU NimbleGen Microarray Facility at Florida State University.

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Wnt/β-catenin activation cooperates with loss of p53 to cause adrenocortical carcinoma in mice.

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