Anx7 Is Required for Nutritional Control of Gene Expression in Mouse Pancreatic Islets of Langerhans

Srivastava, Meera; Eidelman, Ofer; Leighton, Ximena; Glasman, Mirta; Goping, G.; Pollard, Harvey B.

doi:10.1007/bf03402083

Cited by 23 publications

(14 citation statements)

References 64 publications

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“…The precise function or functions of C17orf104 have not been described, whereas ITPR3 encodes a calcium channel receptor that binds inositol 1,4,5-trisphosphate, mediates intracellular calcium levels, and is important to exocrine functions that influence metabolism and growth (38,39). ITPR3 has been implicated in breast cancer proliferation, and elevated expression levels correlate with increased invasion and metastasis and decreased survival in colorectal cancer as well as dissemination of gastric cancers (40)(41)(42).…”

Section: Resultsmentioning

confidence: 99%

Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma

Hedberg¹,

Goh²,

Chiosea³

et al. 2015

Journal of Clinical Investigation

155

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BACKGROUND.Recurrence and/or metastasis occurs in more than half of patients with head and neck squamous cell carcinoma (HNSCC), and these events pose the greatest threats to long-term survival. We set out to identify genetic alterations that underlie recurrent/metastatic HNSCC. METHODS.Whole-exome sequencing (WES) was performed on genomic DNA extracted from fresh-frozen whole blood and patient-matched tumor pairs from 13 HNSCC patients with synchronous lymph node metastases and 10 patients with metachronous recurrent tumors. Mutational concordance within and between tumor pairs was used to analyze the spatiotemporal evolution of HNSCC in individual patients and to identify potential therapeutic targets for functional evaluation.RESULTS. Approximately 86% and 60% of single somatic nucleotide variants (SSNVs) identified in synchronous nodal metastases and metachronous recurrent tumors, respectively, were transmitted from the primary index tumor. Genes that were mutated in more than one metastatic or recurrent tumor, but not in the respective primary tumors, include C17orf104, inositol 1,4,5-trisphosphate receptor, type 3 (ITPR3), and discoidin domain receptor tyrosine kinase 2 (DDR2). Select DDR2 mutations have been shown to confer enhanced sensitivity to SRC-family kinase (SFK) inhibitors in other malignancies. Similarly, HNSCC cell lines harboring endogenous and engineered DDR2 mutations were more sensitive to the SFK inhibitor dasatinib than those with WT DDR2. CONCLUSION.In this WES study of patient-matched tumor pairs in HNSCC, we found synchronous lymph node metastases to be genetically more similar to their paired index primary tumors than metachronous recurrent tumors. This study outlines a compendium of somatic mutations in primary, metastatic, and/or recurrent HNSCC cancers, with potential implications for precision medicine approaches. FUNDING.

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Section: Resultsmentioning

confidence: 99%

Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma

Hedberg¹,

Goh²,

Chiosea³

et al. 2015

Journal of Clinical Investigation

155

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“…Neither IGF-1 nor corticosterone levels varied between wild-type or mutant, male or female (14). Moreover, the pituitaries of mutant males and mutant females were not found to be histologically different from wild-type littermate controls.…”

Section: Anx7(؉͞؊) Mice Exhibit Gender Dimorphic Gigantism and Organo-mentioning

confidence: 77%

“…The multiplicity of procarcinogenic genes down-regulated by the Anx7(ϩ͞Ϫ) genotype emphasizes the possible ''gatekeeper'' character of Anx7, much like many other TSGs. We have described such global gatekeeper-like properties of the Anx7(ϩ͞Ϫ) genotype for islets of Langerhans (14).…”

Section: Downstream Members Of Anx7 Signaling Pathway Involved In Tu-mentioning

confidence: 99%

“…For example, with the exception of generalized, gender-independent organomegaly reported for the p27 kip1 (Ϫ͞Ϫ) mouse (33,34), the reported instances of mutation-based gigantism are mostly endocrine in origin and are due to increases of either growth hormone (35), IGF-1 (36), or IGF-2 (37). However, the levels of serum IGF-1 and growth hormone in the Anx7(ϩ͞Ϫ) mouse are within normal limits (14). One qualitative parallel between the growth kinetics of male Anx7(ϩ͞Ϫ) mice and those mice transgenic for growth hormone or IGF-1 is a postpartum delay in the onset of enhanced growth.…”

Section: Downstream Members Of Anx7 Signaling Pathway Involved In Tu-mentioning

confidence: 99%

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Haploinsufficiency of Anx7 tumor suppressor gene and consequent genomic instability promotes tumorigenesis in the Anx7(+/-) mouse

Srivastava

Montagna

Leighton

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Annexin 7 (ANX7) acts as a tumor suppressor gene in prostate cancer, where loss of heterozygosity and reduction of ANX7 protein expression is associated with aggressive metastatic tumors. To investigate the mechanism by which this gene controls tumor development, we have developed an Anx7(؉͞؊) knockout mouse. As hypothesized, the Anx7(؉͞؊) mouse has a cancer-prone phenotype. The emerging tumors express low levels of Anx7 protein. Nonetheless, the wild-type Anx7 allele is detectable in laser-capture microdissection-derived tumor tissue cells. Genome array analysis of hepatocellular carcinoma tissue indicates that the Anx7(؉͞؊) genotype is accompanied by profound reductions of expression of several other tumor suppressor genes, DNA repair genes, and apoptosis-related genes. In situ analysis by tissue imprinting from chromosomes in the primary tumor and spectral karyotyping analysis of derived cell lines identify chromosomal instability and clonal chromosomal aberrations. Furthermore, whereas 23% of the mutant mice develop spontaneous neoplasms, all mice exhibit growth anomalies, including gender-specific gigantism and organomegaly. We conclude that haploinsufficiency of Anx7 expression appears to drive disease progression to cancer because of genomic instability through a discrete signaling pathway involving other tumor suppressor genes, DNA-repair genes, and apoptosis-related genes.hepatocellular carcinoma ͉ lymphosarcoma of the thymus ͉ SKY analysis ͉ cDNA microarray A nnexin 7 (ANX7) is a newly described tumor suppressor gene (TSG) for prostate cancer in men, featuring loss of heterozygosity and reduced ANX7 § protein expression in a large fraction of archived metastatic tumors (1). ANX7 maps to chromosome 10q21, where unknown TSGs had been postulated but not yet identified (2-4). In a previous work, we established an Anx7(ϩ͞Ϫ) knockout mouse, in which Ca 2ϩ -dependent endocrine secretory defects were identified (5). We also noted substantial reductions of Anx7 expression in the pancreas, heart, and other tissues. The nullizygous Anx7(Ϫ͞Ϫ) knockout could not be studied. The embryo failed to develop beyond embryonic day 10 in utero. However, as the Anx7(ϩ͞Ϫ) colony aged, we began to observe an increasing frequency of disparate tumors (6). The mechanism of tumorigenesis in humans and mice often differ (7). Therefore, given the apparent TSG-like ANX7 parallel between tumors in mice and humans, we felt compelled to investigate the mechanisms of tumor transformation in the Anx7(ϩ͞Ϫ) mouse model.Mechanistically, we reasoned that we might be able to distinguish between a Knudson two-hit model, as might be considered possible based on the human prostate tumor data, and a haploinsufficiency model, based on low Anx7 protein levels in otherwise normal knockout-mouse tissues. We find that the data clearly support a haploinsufficiency model for tumor development in the knockout mouse. In addition, the tumors demonstrate an increased level of genetic instability, based on spectral karyotyping (SKY) analysis of primary tumors...

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“…For instance, deficiency of RB1 reduces cell size, whereas PTEN increases cell size. [14][15][16] Growth anomalies in cancer-prone Anxa7(1/2) mice included organomegaly and betacell hypertrophy, 1,17 suggesting that ANXA7 can also be involved in cell size regulation.…”

Section: Anxa7 Protein Affected Cell Viability In Prostate Cancer Celmentioning

confidence: 99%

Annexin‐A7 protects normal prostate cells and induces distinct patterns of RB‐associated cytotoxicity in androgen‐sensitive and ‐resistant prostate cancer cells

Torosyan

Šimáková

Shanmugam

et al. 2009

Intl Journal of Cancer

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The tumor suppressor role of annexin-A7 (ANXA7) was previously demonstrated by cancer susceptibility in Anxa7(1/2)-mice and by ANXA7 loss in human cancers, especially in hormone-resistant prostate tumors. To gain mechanistic insights into ANXA7 tumor suppression, we undertook an in vitro study in which we compared wild-type (WT)-ANXA7 and dominant-negative (DN)-ANXA7 effects to a conventional tumor suppressor p53 in prostate cancer cells with different androgen sensitivity. Unlike p53 (which caused cell growth arrest and apoptosis to a noticeable extent in benign PrEC), WT-ANXA7 demonstrated profound cytotoxicity in androgen-sensitive LNCaP as well as in the androgen-resistant DU145 and PC3 prostate cancer cells, but not in PrEC. In androgen-sensitive LNCaP, WT-ANXA7 decreased lowmolecular-weight (LMW) AR protein forms and maintained higher retinoblastoma 1 (RB1)/phospho-RB1 ratio. In contrast, DN-ANXA7 (which lacks phosphatidylserine liposome aggregation properties) increased LMW-AR forms and hyperphosphorylated RB1 that was consistent with the lack of DN-ANXA7 cytotoxicity. According to the microarray-based Ingenuity Pathways Analysis, a major WT-ANXA7 effect in androgen-sensitive LNCaP constituted of upregulation of the RB1-binding transcription factor E2F1 along with its downstream proapoptotic targets such as ASK1 and ASPP2. These results suggested a reversal of the RBdependent repression of the proapoptotic E2F-mediated transcription. However, DN-ANXA7 increased RB1/2 (but not E2F1) expression and induced the proliferation-promoting ERK5, thereby maintaining the RB-dependent repression of E2F-mediated apoptosis in LNcaP. On the other hand, in androgen-resistant cells, WT-ANXA7 tumor suppressor effects involved PTEN and NFkB pathways. Thus, ANXA7 revived the RB-associated cell survival control and overcame androgen resistance and dysfunctional status of major tumor suppressors commonly mutated in prostate cancer. Published 2009 UICC. This article is a US Government work and, as such, is in the public domain in the United States of America.Key words: annexin-A7 vs. p53; RB-E2F; AR; prostate cancer; Ingenuity Pathways Analysis Annexin-VII (ANXA7 or synexin) is a ubiquitously expressed member of the multifunctional Ca/phospholipid-binding annexin family. In addition to Ca 21 -activated GTPase activity as well as involvement in membrane fusion and exocytosis, ANXA7 demonstrated tumor suppressor function in murine model 1 and in human prostate and breast cancers. 2,3 Our large-scale study on ANXA7 protein expression in different cancers 4 identified a drastic ANXA7 loss in the hormone-refractory prostate cancers as well as an abundant ANXA7 presence in the adrenal gland, a major source of sex hormone precursors. Although tumor suppressor mechanisms of ANXA7 are not yet elucidated, these data suggested that ANXA7, which has androgen-receptor (AR) regulatory elements in its promoter, may be involved in the regulation of androgen-dependent cell survival in prostate cancer cells.Androgen-dependent proliferation is p...

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Anx7 Is Required for Nutritional Control of Gene Expression in Mouse Pancreatic Islets of Langerhans

Cited by 23 publications

References 64 publications

Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma

Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma

Haploinsufficiency of Anx7 tumor suppressor gene and consequent genomic instability promotes tumorigenesis in the Anx7(+/-) mouse

Annexin‐A7 protects normal prostate cells and induces distinct patterns of RB‐associated cytotoxicity in androgen‐sensitive and ‐resistant prostate cancer cells

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