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  • br Acknowledgements This work was supported by grants

    2020-01-21


    Acknowledgements This work was supported by grants from National Natural Science Foundation of China (31772196 and 31301693), the Chinese Ministry of Agriculture (the 948 project no. 2014-S10). Rothamsted Research also receives grant-aided support from the UK Biotechnology and Biological Sciences Research Council (BBSRC).
    Introduction One such cofactor is chloride channel-3 (ClC-3), a member of the superfamily of voltage-gated chloride ion channels that participates in various cellular processes, including physiological and pathophysiological processes. In addition, ClC-3 plays a key role in regulating tumour cell proliferation, migration and invasion. Recently, increasing studies have found that ClC-3 is closely related to the malignant behaviour of cancer cells. In human osteosarcoma (OS) cells, ClC-3 is not only critical in cell proliferation but also an important factor for cell migration [1]. Studies have reported that ClC-3 is involved in promoting migration and invasion of glioma silybin by mediating MMP-3 and MMP-9 expression [2]. Additionally, ClC-3 is involved in the regulation of various signal pathways, such as the TGF-beta/Smad signaling pathway [3], nuclear factor-kappaB pathway [4] and PI3K/Akt/mTOR pathway [5]. A previous study demonstrated that ClC-3 expression levels are increased in cervical cancer lesions and closely related to the progression and prognosis of women with cervical cancer. However, the exact mechanism of ClC-3 in cervical squamous cell carcinoma remains unclear. The PI3K/AKT/mTOR signaling pathway is involved in regulating cell proliferation, apoptosis [6], migration and invasion [7]. Dysfunction of PI3K/AKT/mTOR signaling pathway is closely related to cancer development and therapeutic resistance. Downstream effectors of PI3K/AKT/mTOR include members of the matrix metalloproteinase (MMP) family, which participate in extracellular matrix and basement membrane degradation. MMPs are often activated in multiple cancers, which represents a significant event in cancer progression. Previous studies demonstrated an activated PI3K/Akt/mTOR signaling pathway significantly upregulates MMP-9 expression.
    Materials and methods
    Results
    Discussion In cervical cancer [9], under the hypotonic conditions of cervical cancer cell lines and primary culture of carcinoma cells in situ, the volume-sensitive chloride ion channels were activated, but these channels were not activated in normal cervix and human papillomavirus-immortalized cells. Moreover, the expression of volume-sensitive chloride currents was not associated with positivity for human papillomavirus infection. Several studies demonstrated that ClC-3 plays a role in regulating many cellular functions, including cell volume, proliferation, migration and invasion. ClC-3 is overexpressed in the plasma membrane of human glioma cells, and its activity facilitates glioma cells invasion into normal brain via facilitating dynamic regulation of cell volume [2]. Peng et al. [3] demonstrated that high expression of ClC-3 protein promotes the proliferation, migration and invasion of gastric cancer cells. In addition, high ClC-3 expression is related to adverse clinical pathology indicators and predicted poor prognosis. Nevertheless, silencing ClC-3 protein expression can suppress ovarian cancer cell migration and invasion [10]. Tumour cell migration and invasion are committed steps in tumour metastasis, and the geometrical morphology and volume of tumour cells must change during this process. Chloride ion channels may play a vital role in cell migration and invasion given their ability to coordinate ion and water movement through the plasma membrane. Interestingly, ClC-3 is involved in this process. Li et al. [11] demonstrated that ClC-3 increased endometrial cancer cell migration by promoting Cl− ion transport through the endometrial cancer Cl− channel and causing tumour cell volume changes. Moreover, it is believed that Ca2+-activated K+ channels bound to ClC-3 Cl− channels to release K+ and Cl− ions together with obligatory water, causing glioma cells to rapidly shrink. This shrinkage facilitated cell entry into the narrow twisting extracellular brain space and promoted cell invasion and distant metastasis formation [12], suggesting that ClC-3 may accelerate cell migration and invasion via adjusting cell volume. In the present study, we demonstrated ClC-3 expression was closely related to cervical squamous carcinoma cell migration and invasion. On the other hand, knockout of ClC-3 expression can significantly restrain cervical squamous carcinoma cell migration and invasion. These data suggested ClC-3 might serve as an oncogene in cervical squamous carcinoma and exhibit an association with the progression of cervical squamous carcinoma.