MELK/MPK38 in cancer: from mechanistic aspects to therapeutic strategies

Thangaraj, Karthik; Ponnusamy, Lavanya; Natarajan, Sathan Raj; Manoharan, Ravi

doi:10.1016/j.drudis.2020.09.029

Cited by 21 publications

(17 citation statements)

References 81 publications

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“…PRKAR2B has been reported to be involved in the activation of Wnt/β□catenin along with triggering epithelial to mesenchymal transition leading to metastasis in tumors [79]. Consistent with our findings, these genes have been suggested to be prognostic indicators and therapeutic targets in various cancers including HNSCC [74, 75, 76, 77, 78, 79, 80, 81, 82].…”

Section: Discussionsupporting

confidence: 89%

RNA-sequencing manifests the intrinsic role of MAPKAPK2 in facilitating molecular crosstalk during HNSCC pathogenesis

Soni

Anand

Swarnkar

et al. 2020

Preprint

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Background: Transcriptomic profiling has been pivotal in better comprehending the convoluted biology of tumors including head and neck squamous cell carcinoma (HNSCC). Recently, mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK2/MK2) has been implicated in many human diseases including tumors. We recently reported that MK2 is a critical regulator of HNSCC and functions via modulating the transcript turnover of crucial genes involved in HNSCC pathogenesis. Consequently, to expand our insight into the biological relevance of MK2 and intricate cross-talks in tumor milieu, we conceptualized a comprehensive transcriptome analysis of HNSCC. Results: We performed an extensive transcriptomic profiling to ascertain global patterns of gene expression in both in vitro and in vivo experimental models of HNSCC which exquisitely emulates the tumor microenvironment. Transcriptomic characterization substantiated an intrinsic role of MK2 and certain MK2-regulated genes in HNSCC pathogenesis, an outcome that reiterates our recent findings. Annotation and differential gene expression analysis revealed candidate genes whilst pathway enrichment analysis corroborated the biological significance of findings. Furthermore, advanced gene expression assays through nCounter system (primary validation) in conjunction with immunohistochemical analysis (secondary validation) validated the transcriptome profiling outcomes quite robustly. Conclusions: Our results have underpinned the importance of seven differentially expressed MK2-regulated genes which are constitutively involved in HNSCC pathogenesis and could serve as potential candidates for future endeavors pertaining to therapeutic interventions and diagnosis pertaining to HNSCC. Collectively, our findings have paved the way towards the identification and development of new effective tumor markers and potential molecular targets for HNSCC management and improved clinical outcomes.

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Section: Discussionsupporting

confidence: 89%

RNA-sequencing manifests the intrinsic role of MAPKAPK2 in facilitating molecular crosstalk during HNSCC pathogenesis

Soni

Anand

Swarnkar

et al. 2020

Preprint

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“…Liu et al recently disclosed that MELK facilitated colorectal cancer progression by activating FAK/Src pathway [44]. MELK is reported to be involved in multiple cellular events in tumorigenesis and malignant progression of human cancers by phosphorylation and regulation of several signaling molecules [45], such as NF-κB [46] and mTOR [47]. Thus, more detailed investigation on the downstream signaling pathways of MELK is required in NSCLC.…”

Section: Discussionmentioning

confidence: 99%

KLF5-induced BBOX1-AS1 contributes to cell malignant phenotypes in non-small cell lung cancer via sponging miR-27a-5p to up-regulate MELK and activate FAK signaling pathway

Shi

Yang

et al. 2021

J Exp Clin Cancer Res

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Background Non-small cell lung cancer (NSCLC) is a major histological subtype of lung cancer with high mortality and morbidity. A substantial amount of evidence demonstrates long non-coding RNAs (lncRNA) as critical regulators in tumorigeneis and malignant progression of human cancers. The oncogenic role of BBOX1 anti-sense RNA 1 (BBOX1-AS1) has been reported in several tumors. As yet, the potential functions and mechanisms of BBOX1-AS1 in NSCLC are obscure. Methods The gene and protein expression was detected by qRT-PCR and western blot. Cell function was determined by CCK-8, colony forming, would healing and transwell assays. Bioinformatics tools, ChIP assays, dual luciferase reporters system and RNA pull-down experiments were used to examine the interaction between molecules. Subcutaneous tumor models in nude mice were established to investigate in vivo NSCLC cell behavior. Results BBOX1-AS1 was highly expressed in NSCLC tissues and cells. High BBOX1-AS1 expression was associated with worse clinical parameters and poor prognosis. BBOX1-AS1 up-regulation was induced by transcription factor KLF5. BBOX1-AS1 deficiency resulted in an inhibition of cell proliferation, migration, invasion and EMT in vitro. Also, knockdown of BBOX1-AS1 suppressed NSCLC xenograft tumor growth in mice in vivo. Mechanistically, BBOX1-AS1 acted act as a competetive “sponge” of miR-27a-5p to promote maternal embryonic leucine zipper kinase (MELK) expression and activate FAK signaling. miR-27a-5p was confirmed as a tumor suppressor in NSCLC. Moreover, BBOX1-AS1-induced increase of cell proliferation, migration, invasion and EMT was greatly reversed due to the overexpression of miR-27a-5p. In addition, the suppressive effect of NSCLC progression owing to BBOX1-AS1 depletion was abated by the up-regulation of MELK. Consistently, BBOX1-AS1-mediated carcinogenicity was attenuated in NSCLC after treatment with a specific MELK inhibitor OTSSP167. Conclusions KLF5-induced BBOX1-AS1 exerts tumor-promotive roles in NSCLC via sponging miR-27a-5p to activate MELK/FAK signaling, providing the possibility of employing BBOX1-AS1 as a therapeutic target for NSCLC patients.

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“…In our study, we determined that MELK and xCT were strongly colocalized in CRC cells using IF staining and that the expression of MELK was regulated by xCT. In recent years, many studies have shown that MELK is upregulated in multiple types of human tumors including lung, breast, and gastric cancers [ 31 , 32 ], the effect of RNAi-mediated MELK knockout has confirmed that MELK expression is essential for the proliferation and invasion of cancer cells [ 33 ]. Interestingly, when analyzing the role of the Akt/mTOR signaling pathway in the tumorigenesis and stemness of cancer, we found previous studies indicating that high MELK expression can activate the mTORC1 and mTORC2/AKT signaling pathways and promote the development of endometrial cancer (EC) [ 5 ].…”

Section: Discussionmentioning

confidence: 99%

xCT contributes to colorectal cancer tumorigenesis through upregulation of the MELK oncogene and activation of the AKT/mTOR cascade

et al. 2022

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Colorectal cancer (CRC) is one of the most commonly diagnosed and deadly malignant tumors globally, and its occurrence and progression are closely related to the poor histological features and complex molecular characteristics among patients. It is urgent to identify specific biomarkers for effective treatment of CRC. In this study, we performed comprehensive experiments to validate the role of xCT expression in CRC tumorigenesis and stemness and confirmed xCT knockdown significantly suppressed the proliferation, migration, and stemness of CRC cells in vitro and effectively inhibited CRC tumorigenesis and metastasis in vivo. In addition, bioinformatic analysis and luciferase assays were used to identify E2F1 as a critical upstream transcription factor of SLC7A11 (the gene encoding for xCT) that facilitated CRC progression and cell stemness. Subsequent RNA sequencing, western blotting, rescue assay, and immunofluorescence assays revealed MELK directly co-expressed with xCT in CRC cells, and its upregulation significantly attenuated E2F1/xCT-mediated tumorigenesis and stemness in CRC. Further molecular mechanism exploration confirmed that xCT knockdown may exert an antitumor effect by controlling the activation of MELK-mediated Akt/mTOR signaling. Erastin, a specific inhibitor of xCT, was also proven to effectively inhibit CRC tumorigenesis and cell stemness. Altogether, our study showed that E2F1/xCT is a promising therapeutic target of CRC that promotes tumorigenesis and cell stemness. Erastin is also an effective antitumoral agent for CRC.

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MELK/MPK38 in cancer: from mechanistic aspects to therapeutic strategies

Cited by 21 publications

References 81 publications

RNA-sequencing manifests the intrinsic role of MAPKAPK2 in facilitating molecular crosstalk during HNSCC pathogenesis

RNA-sequencing manifests the intrinsic role of MAPKAPK2 in facilitating molecular crosstalk during HNSCC pathogenesis

KLF5-induced BBOX1-AS1 contributes to cell malignant phenotypes in non-small cell lung cancer via sponging miR-27a-5p to up-regulate MELK and activate FAK signaling pathway

xCT contributes to colorectal cancer tumorigenesis through upregulation of the MELK oncogene and activation of the AKT/mTOR cascade

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