The Ca<sup>2+</sup>‐activated Cl<sup>−</sup> channel, ANO1 (TMEM16A), is a double‐edged sword in cell proliferation and tumorigenesis

Qu, Zhe; Yao, Weicheng; Yao, Ruyong; Liu, Xiangping; Yu, Kuai; Hartzell, Criss

doi:10.1002/cam4.232

Cited by 75 publications

(65 citation statements)

References 61 publications

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“…Outside of the GI tract, Ano1 is present in the vascular smooth muscle (3,36), salivary glands, thyroid, pancreas, prostate, and urinary and gall bladders (29). 11q13 chromosome amplification and subsequent Ano1 overexpression are indicators of poor prognosis for a variety of tumors (1,19,27,40).…”

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confidence: 99%

A novel exon in the human Ca²⁺-activated Cl⁻ channel Ano1 imparts greater sensitivity to intracellular Ca²⁺

Strege

Bernard

Mazzone

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Anoctamin 1 (Ano1; TMEM16A) is a Ca2+-activated Cl− channel (CACC) expressed in interstitial cells of Cajal. The mechanisms by which Ca2+ regulates Ano1 are incompletely understood. In the gastrointestinal tract, Ano1 is required for normal slow wave activity and is involved in regulating cell proliferation. Splice variants of Ano1 have varying electrophysiological properties and altered expression in disease states. Recently, we identified a transcript for human Ano1 containing a novel exon-“exon 0” upstream of and in frame with exon 1. The electrophysiological properties of this longer Ano1 isoform are unknown. Our aim was to determine the functional contribution of the newly identified exon to the Ca2+ sensitivity and electrophysiological properties of Ano1. Constructs with [Ano1(+0)] or without [Ano1(−0)] the newly identified exon were transfected into human embryonic kidney-293 cells. Voltage-clamp electrophysiology was used to determine voltage- and time-dependent parameters of whole cell Cl− currents between isoforms with varying concentrations of intracellular Ca2+, extracellular anions, or Cl− channel inhibitors. We found that exon 0 did not change voltage sensitivity and had no impact on the relative permeability of Ano1 to most anions. Ano1(+0) exhibited greater changes in current density but lesser changes in kinetics than Ano1(−0) in response to varying intracellular Ca2+. The CACC inhibitor niflumic acid inhibited current with greater efficacy and higher potency against Ano1(+0) compared with Ano1(−0). Likewise, the Ano1 inhibitor T16Ainh-A01 reduced Ano1(+0) more than Ano1(−0). In conclusion, human Ano1 containing exon 0 imparts its Cl− current with greater sensitivity to intracellular Ca2+ and CACC inhibitors.

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confidence: 99%

A novel exon in the human Ca²⁺-activated Cl⁻ channel Ano1 imparts greater sensitivity to intracellular Ca²⁺

Strege

Bernard

Mazzone

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…On the other hand, in MASC, some authors also found luminal ACC acinic cell carcinoma expression of DOG1 but unlike ACC, such expression was limited to a few areas [13,26]. In general, DOG1 has been studied on two aspects: (a) as a marker with membranous pattern of expression that helps the diagnosis of certain tumors (such as gastrointestinal stromal tumors) and (b) the relationship of its channel function with tumorigenesis as well as with proliferation, migration, and apoptosis resistance of cancer cells [27][28][29]. In salivary tumors, DOG1 has only been analyzed in relation to its utility as a diagnostic marker.…”

Section: Discussionmentioning

confidence: 99%

Lysozyme Expression Can be Useful to Distinguish Mammary Analog Secretory Carcinoma from Acinic Cell Carcinoma of Salivary Glands

Mariano

Gómez

Nascimento

et al. 2016

Head and Neck Pathol

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Lysozyme is an enzymatic marker of acinar and intercalated duct cells of normal salivary glands. The aim of this study was to verify whether lysozyme expression could be useful to distinguish acinic cell carcinoma (ACC) from its main mimic, mammary analog secretory carcinoma (MASC). For comparison, DOG1 expression was analyzed as well. Seventeen cases of ACC, 15 MASC, and 125 other salivary tumors were studied. Lysozyme expression was found in tumor cells as well as in secreted material of MASC (86.6 % of cases) and in ductal cells of epithelial-myoepithelial carcinoma (EMC-53.8 %), pleomorphic adenoma (PA-29.1 %) and polymorphous lowgrade adenocarcinoma (PLGA-23.8 %). However, in ACC, lysozyme was not expressed. Three patterns of DOG1 staining were seen: apical-luminal, cytoplasmic, and mixed cytoplasmic/membranous. The apical-luminal pattern was detected in ductal cells of ACC (58.8 % of cases), EMC (38.4 %), adenoid-cystic carcinoma (AdCC-35.3 %), PA (8.3 %), and PLGA (4.8 %). These tumors also showed mixed membranous/cytoplasmic staining for DOG1. MASC, mucoepidermoid, and salivary duct carcinomas exhibited only DOG1 cytoplasmic staining. In conclusion, lysozyme cannot be used as a marker of acinar differentiation in salivary tumors. However, lysozyme expression can be helpful to distinguish MASC from ACC due to its high frequency in the former and absence in ACC. It is likely that in MASC, lysozyme expression may reflect a lactational-like secretory differentiation since lysozyme belongs to breast milk proteins. Regarding DOG1 expression, the apical-luminal pattern is related to acinar and intercalated duct differentiation whereas the cytoplasmic staining does not seem to be associated with a specific cellular phenotype.

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“…ANO1 also behaved similarly in cancer cells or tissues, playing different roles in proliferation in different cancer cell types, e.g., ANO1 promotes cell proliferation in many cancer tissues [7] but in one liver cancer cell line it could dramatically prohibit cell proliferation (data not shown).…”

Section: Ano1 Located To Different Vessel Beds May Play Different Rolmentioning

confidence: 97%

“…Since the endogenous CaCC channelsin mammals were identified as the products expressed by ANO1 (anoctamin1) or TMEM16A (transmembrane member 16a) gene in 2008 [4][5][6] , major progresses have been made in the study of various aspects of CaCC-mediated physiological functions and phenomena in mammals [1][2][3]7] . Among the progresses, the channel identification outstandingly contributes to the elucidation of its roles in vascular functions [3,8] .…”

Section: Camentioning

confidence: 99%

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Functions of ANO1/TMEM16A, Ca2+-activated Cl- channels in Regulation of Blood Pressure and Vascular Remodeling

Wang

Zhang

et al. 2016

Journal of Cardiology and Therapy

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Since the molecule of Ca 2+ -activated Cl -channels (CaCC) had been identified as ANO1, major progresses have been made in recent studies on its roles in vascular functions. ANO1 has been confirmed to represent the CaCC channels in vascular smooth myocytes (VSMCs). Generally, ANO1 expresses more in resistance-size small arteries. When activated, it functions to control the VSMC membrane potentials by depolarization. As a result, the voltage-dependent Ca 2+ channel is opened, leading to Ca 2+ entry and VSMC contraction. Thus, the function of ANO1 is important for maintenance of normal blood pressure. Under influence of agonists, e.g., angiotensin II, ANO1 also participates in VSMC differentiation and remodeling which are mediated by KLF5, myocardin and SRF. The factors regulate the transcription of the ANO1 gene and other genes for VSMC differentiation and proliferation.

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The Ca²⁺‐activated Cl⁻ channel, ANO1 (TMEM16A), is a double‐edged sword in cell proliferation and tumorigenesis

Cited by 75 publications

References 61 publications

A novel exon in the human Ca²⁺-activated Cl⁻ channel Ano1 imparts greater sensitivity to intracellular Ca²⁺

A novel exon in the human Ca²⁺-activated Cl⁻ channel Ano1 imparts greater sensitivity to intracellular Ca²⁺

Lysozyme Expression Can be Useful to Distinguish Mammary Analog Secretory Carcinoma from Acinic Cell Carcinoma of Salivary Glands

Functions of ANO1/TMEM16A, Ca2+-activated Cl- channels in Regulation of Blood Pressure and Vascular Remodeling

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The Ca2+‐activated Cl− channel, ANO1 (TMEM16A), is a double‐edged sword in cell proliferation and tumorigenesis

Cited by 75 publications

References 61 publications

A novel exon in the human Ca2+-activated Cl− channel Ano1 imparts greater sensitivity to intracellular Ca2+

A novel exon in the human Ca2+-activated Cl− channel Ano1 imparts greater sensitivity to intracellular Ca2+

Lysozyme Expression Can be Useful to Distinguish Mammary Analog Secretory Carcinoma from Acinic Cell Carcinoma of Salivary Glands

Functions of ANO1/TMEM16A, Ca2+-activated Cl- channels in Regulation of Blood Pressure and Vascular Remodeling

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The Ca²⁺‐activated Cl⁻ channel, ANO1 (TMEM16A), is a double‐edged sword in cell proliferation and tumorigenesis

A novel exon in the human Ca²⁺-activated Cl⁻ channel Ano1 imparts greater sensitivity to intracellular Ca²⁺

A novel exon in the human Ca²⁺-activated Cl⁻ channel Ano1 imparts greater sensitivity to intracellular Ca²⁺