Transmembrane protein 121 as a novel inhibitor of cervical cancer metastasis

Exp Ther Med. 2022 Jul 15;24(3):572. doi: 10.3892/etm.2022.11509. eCollection 2022 Sep.

Abstract

Transmembrane protein 121 (TMEM121) is isolated from the chicken heart using subtraction hybridisation. A previous study by the authors indicated that TMEM121 is highly expressed in adult mouse hearts and acts as an inhibitor of pathological cardiac hypertrophy. In the present study, the association between TMEM121 and cancer was investigated using bioinformatics tools, including Tumour Immune Estimation Resource (TIMER) 2.0, cBioPortal, LinkedOmics analysis, Kaplan-Meier plotter and UALCAN analysis. The expression, genetic variation, gene interaction network and co-expression pattern of TMEM121 in tumours were analysed. The results revealed that TMEM121 was expressed in various tumours and significantly downregulated in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) when compared with its expression in paracancerous tissues, whereas the methylation level of its promoter was increased in tumour tissues. Additionally, associations between TMEM121 and the PI3K/AKT signalling pathway, as well as the expression of cancer-related molecules, were detected. The aforementioned bioinformatics analysis suggests that TMEM121 may be involved in the development of cervical cancer. Therefore, gain-of-function and loss-of-function experiments in HeLa cells were conducted to verify the role of TMEM121 in cervical cancer. The assay using Cell Counting Kit-8 (CCK-8) revealed that the cell viability of HeLa cells with TMEM121 overexpression was significantly reduced. High TMEM121 expression inhibited HeLa cell migration, as indicated by the decrease in the cell scratch healing rate. The western blot assay revealed that TMEM121 overexpression downregulated the expression of B-cell lymphoma 2 (BCL-2), cyclin D1, cyclin E2 and phosphorylated (p)-AKT, while upregulating that of p27, E-cadherin and p-p38. When TMEM121 was knocked down, retinoblastoma protein (RB), p53, p27, E-cadherin, p-JNK and p-p38 were inhibited, but cyclin E1 was promoted. By combining bioinformatics and experimental biology in the present study, the results demonstrated for the first time, to the best of our knowledge, that TMEM121 may be a novel inhibitor of cervical cancer that is linked to multiple signalling pathways, paving the way for the development of novel diagnostic and therapeutic strategies.

Keywords: PI3K/AKT signaling pathway; cell migration; cervical cancer; inhibitor; transmembrane protein 121.

Grants and funding

Funding: The present study was supported by grants from the National Natural Science Foundation of China (grant nos. 81670290, 81801392, 32071175, 31572349, 81370230, 81570279, 81974019 and 81600320), the National Key Research and Development Program of China (grant nos. 2018YFA0108700 and 2017YFA0105602), the NSFC Projects of International Cooperation and Exchanges (grant no. 81720102004), The Research Team Project of Natural Science Foundation of Guangdong Province of China (grant no. 2017A030312007), the Science and Technology Planning Project of Guangdong Province (grant no. 2022B1212010010), the Key Program of Guangzhou Science Research Plan (grant no. 201904020047), The Special Project of Dengfeng Program of Guangdong Provincial People's Hospital (grant nos. DFJH201812, KJ012019119 and KJ012019423) and the Hunan Provincial Natural Science Foundation of China (grant no. 2020JJ5354).