AHNAK enables mammary carcinoma cells to produce extracellular vesicles that increase neighboring fibroblast cell motility

Silva, Thaiomara A.; Smuczek, Basilio; Valadão, Iuri Cordeiro; Dzik, Luciana Machado; Iglesia, Rebeca Piatniczka; Cruz, Mário Costa; Zelanis, André; Siqueira, Adriane Sousa de; Serrano, Solange M.T.; Goldberg, Gary S.; Jaeger, Ruy Gastaldoni; Freitas, Vanessa M.

doi:10.18632/oncotarget.10307

Cited by 47 publications

(37 citation statements)

References 37 publications

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“…There are obvious differences in AHNAK expression in different cancers. Concerning the present findings, the expression of AHNAK is down-regulated in human breast cancer 12 , melanoma 21 , Burkitt lymphoma, colon carcinoma, and neuroblastoma 9 ; but up-regulated in mesothelioma 22 , laryngeal carcinoma 23 and invasive ductal carcinoma 24 . Meanwhile, researches showed that AHNAK mutation was considered as a prognostic factor related to the poor survival of patients with melanoma 21 , laryngeal carcinoma 23 , triple-negative breast cancer 25 and glioblastoma 26 .…”

Section: Introductionsupporting

confidence: 47%

“…Similarly, knockdown of AHNAK resulted in decreased migration and invasion in the mesothelioma cell lines 22 . Meanwhile, AHNAK enabled mammary carcinoma cells to produce extracellular vesicles that increase neighboring fibroblast cell motility 24 . On the contrary of the above-mentioned studies which AHNAK was considered as an oncogenic protein, it also has been demonstrated to play a role of a tumor suppressor.…”

Section: Discussionmentioning

confidence: 99%

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AHNAK as a Prognosis Factor Suppresses the Tumor Progression in Glioma

Zhao¹,

Xiao²,

Yuan

et al. 2017

J. Cancer

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Purpose: AHNAK is originally identified as a giant protein based on the estimated size of approximately 700 kDa. The aim of this study is to identify the role of AHNAK in the pathogenesis of glioma.Methods: We tested AHNAK mRNA level in a panel of six human glioma cell lines, and in 30 cases of normal brain tissues and 73 cases of glioma tissue samples using a qRT-PCR method. Further, we analyzed the relationship of AHNAK expression with clinicopathological characteristics in glioma patients. Meanwhile, we analyzed the relationship of expression of AHNAK and survival of glioma patients in survival analyses. Then, in vitro, we analyzed the biological effects of AHNAK in glioma cell lines (U87 and U251) including proliferation assay, cell transwell assay, and apoptosis. And in vivo, we examined the effects of AHNAK on tumor growth using xenograft model of human glioma cells in nude mice. Then we examined the expression of Ki-67-positive cells in these tumors.Results: We found that the mRNA levels of AHNAK were down-regulated in 4 of 6 human glioma cell lines, especially in U87 and U251 cell lines. Meanwhile, in glioma patients, a negative correlation was found between the expression of AHNAK and the glioma histopathology. And a low expression of AHNAK was a significant and independent prognostic factor for poor survival of glioma patients. Through over expression of AHNAK in both of U87 and U251, we demonstrated that overexpression of AHNAK could inhibit glioma cell proliferation and invasion, induce apoptosis, and inhibit in vivo glioma tumor growth and ki-67 expression.Conclusions: The AHNAK acts as a potential tumor suppressor. Our study provides a preclinical basis for developing AHNAK as a reliable clinical prognostic indicator for glioma patients, and a new biomarker for treatment response, and a potentially therapeutic target in glioma management options.

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Section: Introductionsupporting

confidence: 47%

Section: Discussionmentioning

confidence: 99%

AHNAK as a Prognosis Factor Suppresses the Tumor Progression in Glioma

Zhao¹,

Xiao²,

Yuan

et al. 2017

J. Cancer

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“…The AHNAK family are membrane scaffold proteins (Komuro et al ., ) and markers of Ca 2+ ‐dependent vesicles (enlargosomes), that are rapidly exocytosed upon stimulation and then recycled by endocytosis (Borgonovo et al ., ; Cocucci et al ., ; Lorusso et al ., ). AHNAK contributes to enlargosome formation and release (Borgonovo et al ., ; Lorusso et al ., ; Zacharias et al ., ; Silva et al ., ). The targeting of AHNAK1 to plasma membranes requires interaction with the S100A10/annexin A2 complex (Benaud et al ., ).…”

Section: Interactions Of S100b With Intracellular Target Proteinsmentioning

confidence: 97%

The Zn²⁺ and Ca²⁺‐binding S100B and S100A1 proteins: beyond the myths

2020

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The S100 genes encode a conserved group of 21 vertebrate-specific EF-hand calcium-binding proteins. Since their discovery in 1965, S100 proteins have remained enigmatic in terms of their cellular functions. In this review, we summarize the calcium-and zinc-binding properties of the dimeric S100B and S100A1 proteins and highlight data that shed new light on the extracellular and intracellular regulation and functions of S100B. We point out that S100B and S100A1 homodimers are not functionally interchangeable and that in a S100A1/S100B heterodimer, S100A1 acts as a negative regulator for the ability of S100B to bind Zn 2+ . The Ca 2+ and Zn 2+ -dependent interactions of S100B with a wide array of proteins form the basis of its activities and have led to the derivation of some initial rules for S100B recognition of protein targets. However, recent findings have strongly suggested that these rules need to be revisited. Here, we describe a new consensus S100B binding motif present in intracellular and extracellular vertebrate-specific proteins and propose a new model for stable interactions of S100B dimers with full-length target proteins. A chaperone-associated function for intracellular S100B in adaptive cellular stress responses is also discussed. This review may help guide future studies on the functions of S100 proteins in general.Biological Reviews 95 (2020) 738-758

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“…For example, Ahnak functions as a tumor suppressor in breast cancer by inhibiting cell growth via potentiation of the TGFb signaling pathway (11). However, Ahnak is also associated with tumor development and progression (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

AHNAK Loss in Mice Promotes Type II Pneumocyte Hyperplasia and Lung Tumor Development

Park

Kim

Choi

et al. 2018

Molecular Cancer Research

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AHNAK is known to be a tumor suppressor in breast cancer due to its ability to activate the TGFβ signaling pathway. However, the role of AHNAK in lung tumor development and progression remains unknown. Here, the Ahnak gene was disrupted to determine its effect on lung tumorigenesis and the mechanism by which it triggers lung tumor development was investigated. First, AHNAK protein expression was determined to be decreased in human lung adenocarcinomas compared with matched nonneoplastic lung tissues. Then, Ahnak mice were used to investigate the role of AHNAK in pulmonary tumorigenesis. Ahnak mice showed increased lung volume and thicker alveolar walls with type II pneumocyte hyperplasia. Most importantly, approximately 20% of aged Ahnak mice developed lung tumors, and Ahnak mice were more susceptible to urethane-induced pulmonary carcinogenesis than wild-type mice. Mechanistically, Ahnak deficiency promotes the cell growth of lung epithelial cells by suppressing the TGFβ signaling pathway. In addition, increased numbers of M2-like alveolar macrophages (AM) were observed in Ahnak lungs, and the depletion of AMs in Ahnak lungs alleviated lung hyperplastic lesions, suggesting that M2-like AMs promoted the progression of lung hyperplastic lesions in Ahnak-null mice. Collectively, AHNAK suppresses type II pneumocyte proliferation and inhibits tumor-promoting M2 alternative activation of macrophages in mouse lung tissue. These results suggest that AHNAK functions as a novel tumor suppressor in lung cancer. The tumor suppressor function of AHNAK, in murine lungs, occurs by suppressing alveolar epithelial cell proliferation and modulating lung microenvironment. .

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AHNAK enables mammary carcinoma cells to produce extracellular vesicles that increase neighboring fibroblast cell motility

Cited by 47 publications

References 37 publications

AHNAK as a Prognosis Factor Suppresses the Tumor Progression in Glioma

AHNAK as a Prognosis Factor Suppresses the Tumor Progression in Glioma

The Zn²⁺ and Ca²⁺‐binding S100B and S100A1 proteins: beyond the myths

AHNAK Loss in Mice Promotes Type II Pneumocyte Hyperplasia and Lung Tumor Development

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AHNAK enables mammary carcinoma cells to produce extracellular vesicles that increase neighboring fibroblast cell motility

Cited by 47 publications

References 37 publications

AHNAK as a Prognosis Factor Suppresses the Tumor Progression in Glioma

AHNAK as a Prognosis Factor Suppresses the Tumor Progression in Glioma

The Zn2+ and Ca2+‐binding S100B and S100A1 proteins: beyond the myths

AHNAK Loss in Mice Promotes Type II Pneumocyte Hyperplasia and Lung Tumor Development

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Product

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The Zn²⁺ and Ca²⁺‐binding S100B and S100A1 proteins: beyond the myths