Maternal embryonic leucine zipper kinase: A novel biomarker and a potential therapeutic target of cervical cancer

Abstract

Maternal embryo leucine zipper kinase (MELK) is highly expressed in a variety of malignant tumors and involved in cell cycle regulation, cell proliferation, apoptosis, tumor formation etc However, the biological effects of MELK in cervical cancer are still uninvestigated. This study aimed to explore the expression of MELK in cervical cancer, as well as its effects on the proliferation, apoptosis, DNA damage repair on cervical cancer cell line in vitro and to provide novel ideas for further improving the clinical efficacy of cervical cancer. Immunohistochemistry, Western blot, RT‐qPCR, CCK8, and immunofluorescence techniques were used to detect the expression of MELK in cervical cancer tissues, paracancerous tissues, and cervical cancer cell lines. Several cervical cancer cell lines were treated with MELK knockdown by siRNA and MELK selective inhibitor OTSSP167. The effects on proliferation, apoptosis, and colony formation capacity, and tumor cell DNA damage repair‐related factor were detected in cell lines. Our data showed that the high expression rate of MELK in cervical cancer patients was 56.92%. MELK expression in cervical cancer samples was significantly higher than that in paraneoplastic tissues. Highly expressed MELK correlated with the cervical histopathological grading and greatly increased with the cervical histopathological grading, from normal cervix and cervical intraepithelial neoplasia to cervical cancer. Moreover, the abnormal expression of MELK was related to cervical cancer metastasis at early stage. The knockdown of MELK with siRNA and OTSSP167 had strong inhibition effects on the proliferation, apoptosis, and colony formation of cervical cancer cells. MELK knockdown could also aggravate the DNA damage of cervical cancer cells possibly by homologous recombination repair pathway. Therefore, MELK may be a predicting marker of poor prognosis of cervical cancer and may also be a new therapeutic target for cervical cancer, providing ideas for improving the therapeutic effect of cervical cancer.

Inhibition of MELK produces potential anti‐tumour effects in bladder cancer by inducing G1/S cell cycle arrest via the ATM/CHK2/p53 pathway

“…In addition, in accordance with bioinformatics analyses of GSE13507, MELK was involved in the cell cycle, G1/S transition of the mitotic cell cycle, DNA repair and replication, which was similar to previous reports 6,26,33,[39][40][41][42][43]. A, The expression of MELK was up-regulated at transcription level with MELK plasmid; it was down-regulated by OTSSP167.…”

Maternal Embryonic Leucine Zipper Kinase Promotes Tumor Growth and Metastasis via Stimulating FOXM1 Signaling in Esophageal Squamous Cell Carcinoma

“…High MELK protein expression was significantly related with tumor number, tumor size and recurrence. Furthermore, elevated MELK protein expression was correlated with decreased overall survival and disease-free survival in various types of human cancer (9,(17)(18)(19). Notably, it revealed that high MELK protein expression was also significantly associated with higher pathological tumor-nodule-metastasis stage, vascular invasion (16).…”

“…MELK is a serine/threonine kinase that belongs to the member of the AMP-activated protein kinase (AMPK)/sucrose nonfermenting kinase 1 (SNF1) family (8). Unlike most members of this family, MELK is not involved in cellular energy metabolism balance (9). MELK, also known as murine MPK38, was originally discovered by Heyer et al as a signal transduction factor and was predominantly expressed in the mouse egg and preimplantation embryo (10).…”

“…Notably, it revealed that high MELK protein expression was also significantly associated with higher pathological tumor-nodule-metastasis stage, vascular invasion (16). Moreover, the abnormal expression of MELK was related to cervical cancer metastasis at early stage (9). Speers and colleges identified MELK as a potential biomarker of radioresistance and target for radiosensitization in triple-negative breast cancer (TNBC) (20).…”

“…Additionally, MELK overexpression confers radioresistance in ER-positive breast cancer cells with low baseline MELK expression (20). In contrast, knockdown of MELK significantly suppressed tumor cell proliferation, colony formation, stemness, and tumorigenicity, and induced apoptosis, mitosis, and DNA damage both in vitro and in nude mice models in gastric cancer (8), hepatocellular carcinoma (21) and cervical cancer (9). Li et al found that targeting MELK by specific molecule inhibitor drastically diminished gastric cancer cell growth in preclinical GC patient-derived xenograft (PDX) mouse models (14,17).…”