Loss of p53 Expression Correlates with Metastatic Phenotype and Transcriptional Profile in a New Mouse Model of Head and Neck Cancer

Ku, Tony K.S.; Nguyen, Dan C.; Karaman, Mazen W.; Gill, Parkash S.; Hacia, Joseph G.; Crowe, David L.

doi:10.1158/1541-7786.mcr-06-0238

Cited by 34 publications

(32 citation statements)

References 51 publications

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“…This model, which involves treatment of mice with the tumor promoter 9,10-dimethyl-1,2-benzanthracene (DMBA) (Supplemental Figure 7A), recapitulates the features of human SCC, including squamous differentiation, high-level p63 expression ( Figure 6B and Supplemental Figure 7B), and metastasis to local lymph nodes (38). Of note, loss of functional p53 was shown to be a rate-limiting event for tumor formation in this model (38). As shown above, cells derived from these tumors exhibit the same regulation of miR-193* by both endogenous p63 and p73 as do human cells (Figure 2).…”

Section: Control Of Tumor Progression and Chemosensitivity By Mir-193mentioning

confidence: 91%

A microRNA-dependent program controls p53-independent survival and chemosensitivity in human and murine squamous cell carcinoma

Ory

Ramsey²,

Wilson³

et al. 2011

J. Clin. Invest.

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The p53 tumor suppressor, a central mediator of chemosensitivity in normal cells, is functionally inactivated in many human cancers. Therefore, a central challenge in human cancer therapy is the identification of pathways that control tumor cell survival and chemosensitivity in the absence of functional p53. The p53-related transcription factors p63 and p73 exhibit distinct functions -p73 mediates chemosensitivity while p63 promotes proliferation and cell survival -and are both overexpressed in squamous cell carcinomas (SCCs). However, how p63 and p73 interact functionally and govern the balance between prosurvival and proapoptotic programs in SCC remains elusive. Here, we identify a microRNA-dependent mechanism of p63/p73 crosstalk that regulates p53-independent survival of both human and murine SCC. We first discovered that a subset of p63-regulated microRNAs target p73 for inhibition. One of these, miR-193a-5p, expression of which was repressed by p63, was activated by proapoptotic p73 isoforms in both normal cells and tumor cells in vivo. Chemotherapy caused p63/p73-dependent induction of this microRNA, thereby limiting chemosensitivity due to microRNAmediated feedback inhibition of p73. Importantly, inhibiting miR-193a interrupted this feedback and thereby suppressed tumor cell viability and induced dramatic chemosensitivity both in vitro and in vivo. Thus, we have identified a direct, microRNA-dependent regulatory circuit mediating inducible chemoresistance, whose inhibition may provide a new therapeutic opportunity in p53-deficient tumors.

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Section: Control Of Tumor Progression and Chemosensitivity By Mir-193mentioning

confidence: 91%

A microRNA-dependent program controls p53-independent survival and chemosensitivity in human and murine squamous cell carcinoma

Ory

Ramsey²,

Wilson³

et al. 2011

J. Clin. Invest.

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“…Therefore, the microarray or next generation sequencing transcriptome technologies have proven as a valuable source of candidate metastasis-associated genes (6)(7)(8)(9). We recently used the oligonucleotide microarrays to perform high-throughput screening of global gene expression in a chicken metastatic cell line derived from v-src-induced sarcoma and its nonmetastatic subclone (10).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

Kovářová

Plachý

Kosla

et al. 2013

Molecular Cancer Research

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Comparing the gene expression profiles of metastatic and nonmetastatic cells has the power to reveal candidate metastasis-associated genes, whose involvement in metastasis can be experimentally tested. In this study, differentially expressed genes were explored in the v-src-transformed metastatic cell line PR9692 and its nonmetastatic subclone PR9692-E9. First, the contribution of homeodomain only protein X (HOPX) in metastasis formation and development was assessed. HOPX-specific knockdown decreased HOPX expression in the nonmetastatic subclone and displayed reduced cell motility in vitro. Critically, HOPX knockdown decreased the in vivo metastatic capacity in a syngeneic animal model system. Genomic analyses identified a cadre of genes affected by HOPX knockdown that intersected significantly with genes previously found to be differentially expressed in metastatic versus nonmetastatic cells. Furthermore, 232 genes were found in both screens with at least a two-fold change in gene expression, and a number of high-confidence targets were validated for differential expression. Importantly, significant changes were demonstrated in the protein expression level of three metastaticassociated genes (NCAM, FOXG1, and ITGA4), and knockdown of one of the identified HOPX-regulated metastatic genes, ITGA4, showed marked inhibition of cell motility and metastasis formation. These data demonstrate that HOPX is a metastasis-associated gene and that its knockdown decreases the metastatic activity of v-src-transformed cells through altered gene expression patterns.

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“…1,2 It corresponds to 3% of all malignant cancers in the United States, but is much more prevalent in Brazil, where it accounts for 6% of all cancer deaths. 3 Although major advances in surgical, radiation and chemotherapeutic approaches have been made in the last 25 years, these efforts had no significant impact on the survival of patients with advanced HNSCC.…”

Section: Introductionmentioning

confidence: 99%

Phase I trial of DNA-hsp65 immunotherapy for advanced squamous cell carcinoma of the head and neck

et al. 2008

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Considering that mycobacterial heat-shock protein 65 (hsp65) gene transfer can elicit a profound antitumoral effect, this study aimed to establish the safety, maximum-tolerated dose (MTD) and preliminary efficacy of DNA-hsp65 immunotherapy in patients with advanced head and neck squamous cell carcinoma (HNSCC). For this purpose, 21 patients with unresectable and recurrent HNSCC were studied. Each patient received three ultrasound-guided injections at 21-day intervals of: 150, 600 or 400 mg of DNA-hsp65. Toxicity was graded according to CTCAE directions. Tumor volume was measured before and after treatment using computed tomography scan. The evaluation included tumor mass variation, delayed-type hypersensitivity response and spontaneous peripheral blood mononuclear cell proliferation before and after treatment. The MTD was 400 mg per dose. DNAhsp65 immunotherapy was well tolerated with moderate pain, edema and infections as the most frequent adverse effects. None of the patients showed clinical or laboratory alterations compatible with autoimmune reactions. Partial response was observed in 4 out of 14 patients who completed treatment, 2 of which are still alive more than 3 years after the completion of the trial. Therefore, DNA-hsp65 immunotherapy is a feasible and safe approach at the dose of 400 mg per injection in patients with HNSCC refractory to standard treatment. Further studies in a larger number of patients are needed to confirm the efficacy of this novel strategy.

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Loss of p53 Expression Correlates with Metastatic Phenotype and Transcriptional Profile in a New Mouse Model of Head and Neck Cancer

Cited by 34 publications

References 51 publications

A microRNA-dependent program controls p53-independent survival and chemosensitivity in human and murine squamous cell carcinoma

A microRNA-dependent program controls p53-independent survival and chemosensitivity in human and murine squamous cell carcinoma

Downregulation of HOPX Controls Metastatic Behavior in Sarcoma Cells and Identifies Genes Associated with Metastasis

Phase I trial of DNA-hsp65 immunotherapy for advanced squamous cell carcinoma of the head and neck

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