Abstract
BackgroundMetastasis and invasion are crucial in determining the mortality of cervical carcinoma (CC) patients. The epithelial–mesenchymal transition (EMT) is now a universal explanation for the mechanisms of tumor metastasis. Α-chimeric protein (α-chimaerin, CHN1) plays an important role in the regulation of signal transduction and development. However, the molecular regulatory relationships between CHN1 and CC progression in relation to EMT have not yet been identified.MethodsThe expression of CHN1 in CC tissues, adjacent tissues, and lymph node metastases from CC patients was detected by immunohistochemistry. Upregulation and knockdown of CHN1 were achieved by transfection of CC cells. The effect of CHN1 on cell proliferation was determined by CCK-8 and plate clone formation assays. Changes in migration and invasion capabilities were evaluated using scratch migration and transwell invasion assays. The effect of CHN1 overexpression and interference on xenograft tumor growth was determined by tumor weight and pathological analyses. The expression of EMT-related mRNAs was measured by qRT-PCR in transfected CC cells. EMT-related proteins and Akt/GSK-3β/Snail signaling pathway-related proteins were also evaluated by western blotting.ResultsCHN1 was overexpressed in CC tissues and was associated with lymph node metastasis and low survival in CC patients. Overexpression of CHN1 promoted cell proliferation, migration, and invasion in CC cells. In contrast, silencing of CHN1 inhibited these phenomena. Overexpression of CHN1 promoted tumor formation in an in vivo xenograft tumor mouse model, with increased tumor volumes and weights. In addition, CHN1 induced the expression of EMT-related transcription factors, accompanied by the decreased expression of epithelial markers and increased expression of mesenchymal markers. The Akt/GSK-3β/Snail signaling pathway was activated by overexpression of CHN1 in vitro, and activation of this pathway was inhibited by the signaling pathway inhibitor LY294002.ConclusionThese results suggest that CHN1 promotes the development and progression of cervical carcinoma via the Akt/GSK-3β/Snail pathway by inducing EMT.
Highlights
Metastasis and invasion are crucial in determining the mortality of cervical carcinoma (CC) patients
Despite significant efforts for verifying whether epithelial–mesenchymal transition (EMT) reprogramming of tumor epithelial cells depends on the systematic occurrence at multiple regulation levels [6, 9], the exact underlying mechanisms connecting EMT, metastasis, and cervical carcinoma remain to be elucidated for a better understanding of cancer progression and the related therapeutic methods
Strongly positive expression of α-Chimaerin gene (CHN1) was clearly observed in high, medium, and low-differentiation CC tissues (Fig. 1b), with an overall positive rate of 85.5% (53/62), which was notably different from the rate in non-carcinoma tissues (43.5%, 27/62; Table 1)
Summary
Metastasis and invasion are crucial in determining the mortality of cervical carcinoma (CC) patients. CHN1 is widely investigated in neurobiology and is pivotal in neuronal signal transduction, brain development, synaptogenesis, and cognitive ability [12, 16,17,18,19] It is involved in the regulation of T cell adhesion and chemotaxis [20], transmission of signals in tumor progression by connecting cell adhesion and MAP kinase activation in the Drosophila melanogaster model [21], maintenance of epithelial morphology through its function as an apical-specific Rac GTPase activating protein [22], and key regulation of oculomotor axon guidance decisions in zebrafish [23]. Liu et al showed that CHN1 was highly expressed in human cervical cancer tissues and was positively regulated by miR-205; high expression of CHN1 was correlated with lymph node metastasis [29]
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