Knockdown of TMEM16A suppressed MAPK and inhibited cell proliferation and migration in&amp;nbsp;hepatocellular carcinoma

Deng, Liang; Yang, Jihong; Chen, Hongwu; Ma, Bin-Guang; Pan, Kangming; Su, Caikun; Xu, Feifei; Zhang, Jihong

doi:10.2147/ott.s95985

Cited by 35 publications

(32 citation statements)

References 28 publications

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“…Before it was identified as a CaCC, TMEM16A had been found to be amplified in oral cancer, head and neck squamous cell carcinoma (HNSCC), gastrointestinal stromal tumor (GIST), breast cancer, and esophageal squamous cell (ESCC) cancer under other names such as FLJ10261, TAOS1 (tumor amplified and overexpressed sequence 1) and DOG1 (discovered on GISTs protein 1) [ 37 – 41 ]. Recently, TMEM16A has been reported to be highly expressed in many human tumors including breast cancer [ 42 , 43 ], HNSCC [ 44 – 47 ], colorectal cancer (CRC) [ 48 , 49 ], ESCC [ 50 ], lung cancer [ 51 ], hepatocellular carcinoma [ 52 ], prostate cancer [ 53 ], gastric cancer [ 54 , 55 ], and glioma [ 56 ] (Table 1 ).…”

Section: Introductionmentioning

confidence: 99%

“…TMEM16A also activates the Ras-Raf-Mek-ERK1/2 signaling pathway in UM-SCC1 HNSCC cells and T24 bladder cells [ 44 ]. In SMMC-7721 human hepatoma cells, TMEM16A activates the p38 signaling pathway [ 52 ]. TMEM16A activates the NFκB signaling pathway and promotes the gene transcription in glioma cells [ 56 ].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, in ZR75–1 and HCC1954 breast cancer cell lines, the ERK1/2 signaling pathway is activated by TMEM16A overexpression via EGFR and CaMKII [ 42 ]. In SMMC-7721 human hepatoma cells, TMEM16A knockdown reduced the p38 and ERK1/2 phosphorylation, but not JNK phosphorylation, suggesting that TMEM16A activated the p38 and ERK1/2 signaling pathways [ 52 ]. Therefore, it appears that TMEM16A predominantly activates the MAPK/ERK1/2 signaling pathway in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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Cell-specific mechanisms of TMEM16A Ca2+-activated chloride channel in cancer

et al. 2017

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TMEM16A (known as anoctamin 1) Ca2+-activated chloride channel is overexpressed in many tumors. TMEM16A overexpression can be caused by gene amplification in many tumors harboring 11q13 amplification. TMEM16A expression is also controlled in many cancer cells via transcriptional regulation, epigenetic regulation and microRNAs. In addition, TMEM16A activates different signaling pathways in different cancers, e.g. the EGFR and CAMKII signaling in breast cancer, the p38 and ERK1/2 signaling in hepatoma, the Ras-Raf-MEK-ERK1/2 signaling in head and neck squamous cell carcinoma and bladder cancer, and the NFκB signaling in glioma. Furthermore, TMEM16A overexpression has been reported to promote, inhibit, or produce no effects on cell proliferation and migration in different cancer cells. Since TMEM16A exerts different roles in different cancer cells via activation of distinct signaling pathways, we try to develop the idea that TMEM16A regulates cancer cell proliferation and migration in a cell-dependent mechanism. The cell-specific role of TMEM16A may depend on the cellular environment that is predetermined by TMEM16A overexpression mechanisms specific for a particular cancer type. TMEM16A may exert its cell-specific role via its associated protein networks, phosphorylation by different kinases, and involvement of different signaling pathways. In addition, we discuss the role of TMEM16A channel activity in cancer, and its clinical use as a prognostic and predictive marker in different cancers. This review highlights the cell-type specific mechanisms of TMEM16A in cancer, and envisions the promising use of TMEM16A inhibitors as a potential treatment for TMEM16A-overexpressing cancers.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cell-specific mechanisms of TMEM16A Ca2+-activated chloride channel in cancer

et al. 2017

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“…Some studies have shown that TMEM16A is closely related to the apoptosis of cancer (Wilkerson and Reis-Filho 2013), suggesting that TMEM16A may be a potential biomarker of some aggressive diseases (Deng et al 2016;Song et al 2018;Frobom et al 2019). For normal cells of the body, such as podocytes (Lian et al 2017) and smooth muscle cells Zeng et al 2019), overexpression of TMEM16A can promote apoptosis of these cells and further lead to the occurrence of disease.…”

Section: Discussionmentioning

confidence: 99%

Estrogen inhibits apoptosis of pericytes in the cochlea stria vascularis through downregulating TMEM16A

Zhang

Chen

Feng

et al. 2020

Preprint

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Background: Currently, the specific mechanism of estrogen (E2) in protecting presbycusis is not clear. This study aimed to investigate whether E2 could affect the apoptosis of capillary pericytes (PCs) of cochlear stria vascularis (SV) in aged C57BL/6J mice by regulating transmembrane member 16A (TMEM16A), such that it plays a protective role in presbycusis.Methods: The model of C57BL/6J ovariectomized mice was established, and E2 was administered for 2 months. The hearing threshold was measured by auditory brainstem response (ABR). The changes in the cochlea were measured using hematoxylin-eosin (HE) and electron microscopy. qRT-PCR was used to examine the expression of TMEM16A and apoptosis-related protein mRNA. The PCs were cultured in vitro, and the cell senescence model was established by the continuous passage method. TMEM16A expression was assessed using immunofluorescence. Flow cytometry was performed to explore the apoptosis rate.Results: The results of animal experiments showed that E2 intervention could reduce hearing loss and improve the atrophy of cochlear SV, loss of PC chromatin organelles, cytoplasmic swelling and nuclear porosity in aged mice. E2 also decreased the mRNA expression of TMEM16A, Caspase-3 and Bax in cochlear SV of aged mice and upregulated the expression of Bcl-2 mRNA. Cellular experiments showed that E2 could downregulate the expression of TMEM16A, and E2 or T16Ainh-A01(a specific blocker of TMEM16A) could reduce the apoptosis rate of PCs in aged mice.Conclusions: E2 may inhibit the apoptosis of PCs through downregulating the expression of TMEM16A, which plays a protective role in presbycusis. This study may provide a novel potential treatment and prevention method for presbycusis.

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“…The expression and function of TMEM16A vary with cell type. Some studies have shown that TMEM16A can aggravate the disease by inhibiting apoptosis in cancer and tumors, suggesting that TMEM16A may be a potential biomarker of some aggressive diseases (Deng et al 2016;Song et al 2018;Frobom et al 2019). For normal cells of the body, such as podocytes (Lian et al 2017) and smooth muscle cells (Lian et al 2017), overexpression of TMEM16A can promote apoptosis of these cells and further lead to the occurrence of disease.…”

Section: Discussionmentioning

confidence: 99%

Estrogen inhibits apoptosis of pericytes in the cochlea stria vascularis through downregulating TMEM16A

Zhang

Chen

Feng

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Cochlear cell apoptosis is an important factor influencing presbycusis. Estrogen has a protective effect on hearing, but the specific mechanism of its protective effect on presbycusis is not clear. We studied whether estrogen affects apoptosis by regulating TMEM16A, thus preventing presbycusis. Methods: In an animal model, the hearing threshold was detected by auditory brainstem response (ABR). HE and transmission electron microscopy was used to observe morphological changes. qRT-PCR was used to analyze mRNA level changes. In experiments with cells, primary culture and identification of PCs in the cochlear stria vascularis (SV) were performed. The expression of TMEM16A was detected by immunofluorescence, and the apoptosis rate was detected by flow cytometry. Results: The results showed that estrogen intervention could improve presbycusis, cochlear SV atrophy and PCs degeneration in aged mice, and it could reduce expression of TMEM16A and apoptosis. In addition, experiments with cells showed that TMEM16A expression and apoptosis were increased in the aging cell group, but these effects were reversed by estrogen or T16Ainh-A01 intervention.Conclusions: These results show that estrogen might reduce the apoptosis of PCs by downregulating TMEM16A, which would then protect against hearing loss via presbycusis. This study may provide a novel potential treatment and prevention method for presbycusis.* Xuerui Li and Yang Zhang contributed equally to this work.

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Knockdown of TMEM16A suppressed MAPK and inhibited cell proliferation and migration in hepatocellular carcinoma

Cited by 35 publications

References 28 publications

Cell-specific mechanisms of TMEM16A Ca2+-activated chloride channel in cancer

Cell-specific mechanisms of TMEM16A Ca2+-activated chloride channel in cancer

Estrogen inhibits apoptosis of pericytes in the cochlea stria vascularis through downregulating TMEM16A

Estrogen inhibits apoptosis of pericytes in the cochlea stria vascularis through downregulating TMEM16A

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