Expression of Maternal Embryonic Leucine Zipper Kinase (MELK) Correlates to Malignant Potentials in Hepatocellular Carcinoma

Hiwatashi, Kiyokazu; Ueno, S.; Shimada, Masahiko; Iino, Satoshi; Minami, Koji; Yonemori, Keiichi; Nishizono, Yuka; Kurahara, Hiroshi; Mataki, Yuko; Maemura, Kosei; Shinchi, Hiroyuki

doi:10.21873/anticanres.11088

Cited by 17 publications

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“…Additionally, high MELK expression at the RNA level was associated with low OS and the difference was significant ( Figure 1C, 1D ). These results are consistent with previous reports [ 13 , 22 ]. Second, we further validated them by qRT-PCR analysis in an independent and random cohort of HCC samples consisting of 32 hepatocellular liver tissues and adjacent liver tissues ( Figure 2A ).…”

Section: Discussionsupporting

confidence: 94%

“…Increasing evidence proves that various genes up-regulated or down-regulated in hepatocellular liver tissues can be considered as special prognostic markers and therapeutic targets [ 21 ]. Recent studies reported that MELK expression is increased in many digestive malignant tumors, such as gastric [ 12 ], hepatocellular [ 13 ], and colorectal [ 14 ] tumors. Additionally, high MELK expression indicates poor clinical outcome [ 12 , 13 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies reported that MELK expression is increased in many digestive malignant tumors, such as gastric [ 12 ], hepatocellular [ 13 ], and colorectal [ 14 ] tumors. Additionally, high MELK expression indicates poor clinical outcome [ 12 , 13 ]. Notably, a study recently revealed that MELK mRNA in HCC tissues, collected from a Japanese population, exhibited significantly high expression levels compared with paired normal liver tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, a study recently revealed that MELK mRNA in HCC tissues, collected from a Japanese population, exhibited significantly high expression levels compared with paired normal liver tissues. Moreover, low expression of MELK mRNA predicted longer OS and DFS in HCC patients [ 13 ]. Similarly, a Singaporean study demonstrated that MELK was an oncogenic kinase and overexpression of its RNA was strongly correlated with early recurrence and poor patient survival [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, it was proved to be correlated with cell proliferation, apoptosis, cell renewal, and oncogenesis [ 7 ]. In recent years, although 2 studies reported MELK was not necessary for the proliferation or fitness of basal-like breast cancer cells [ 8 , 9 ], numerous studies indicated MELK plays a crucial role in regulating the genesis and development of several human malignancies, including ovarian [ 10 ], breast [ 11 ], gastric [ 12 ], hepatocellular [ 13 ], and colorectal [ 14 ] cancers. Moreover, increased MELK expression was closely related to the poor prognosis of patients with these cancers [ 10 , 12 , 13 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Up-Regulated Maternal Embryonic Leucine Zipper Kinase Predicts Poor Prognosis of Hepatocellular Carcinoma Patients in a Chinese Han Population

Chen

et al. 2017

Med Sci Monit

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BackgroundMaternal embryonic leucine zipper kinase (MELK) has been implicated in various types of tumors, but its expression profile and clinicopathologic significance in hepatocellular carcinoma (HCC) in Chinese Han people remains unknown. Therefore, this study attempted to investigate the expression pattern of MELK in HCC tissues obtained from a Chinese Han population.Material/MethodsThe expression of MELK, from RNA to protein levels, in HCC or disease-free human liver tissues was evaluated using quantitative real-time polymerase chain reaction assays and immunohistochemistry staining, and its prognostic significance was determined based on its impact on HCC patients’ survival.ResultsWe found that HCC tissues expressed a higher level of MELK RNA than non-tumor tissues in tumor-related public databases (P<0.001). Hence, we assessed MELK mRNA expression within 32 HCC samples and their adjacent non-tumorous liver tissues in our center. Subsequently, MELK protein expression was evaluated within 101 HCC specimens and 40 disease-free liver tissues. Notably, it revealed that high MELK protein expression was significantly related with tumor number, tumor size, higher pathological tumor-nodule-metastasis stage, vascular invasion, and recurrence (P<0.05, all). Furthermore, elevated MELK protein expression was correlated with decreased overall survival and disease-free survival (P=0.004 and P=0.002, respectively). Univariate and multivariate analysis results show that MELK protein may serve as an independent prognostic indicator for determining prognosis of HCC patients.ConclusionsWe found that, in a Chinese Han population, MELK was highly expressed within HCC tissues from RNA to protein levels, and may be a potential independent prognostic biomarker for HCC patients.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Up-Regulated Maternal Embryonic Leucine Zipper Kinase Predicts Poor Prognosis of Hepatocellular Carcinoma Patients in a Chinese Han Population

Chen

et al. 2017

Med Sci Monit

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Prognostic genes of hepatocellular carcinoma based on gene coexpression network analysis

et al. 2019

J of Cellular Biochemistry

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Hepatocellular carcinoma (HCC) is the most common subtype in liver cancer whose prognosis is affected by malignant progression associated with complex gene interactions. However, there is currently no available biomarkers associated with HCC progression in clinical application. In our study, RNA sequencing expression data of 50 normal samples and 374 tumor samples was analyzed and 9225 differentially expressed genes were screened. Weighted gene coexpression network analysis was then conducted and the blue module we were interested was identified by calculating the correlations between 17 gene modules and clinical features. In the blue module, the calculation of topological overlap was applied to select the top 30 genes and these 30 genes were divided into the green group (11 genes) and the yellow group (19 genes) through searching whether these genes were validated by in vitro or in vivo experiments. The genes in the green group which had never been validated by any experiments were recognized as hub genes. These hub genes were subsequently validated by a new data set GSE76427 and KM Plotter Online Tool, and the results indicated that 10 genes (FBXO43, ARHGEF39, MXD3, VIPR1, DNASE1L3, PHLDA1, CSRNP1, ADR2B, C1RL, and CDC37L1) could act as prognosis and progression biomarkers of HCC. In summary, 10 genes who have never been mentioned in HCC were identified to be associated with malignant progression and prognosis of patients. These findings may contribute to the improvement of the therapeutic decision, risk stratification, and prognosis prediction for HCC patients. K E Y W O R D S biomarker, hepatocellular carcinoma, malignant progression, weighted gene coexpression network analysis

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Inhibition of maternal embryonic leucine zipper kinase with OTSSP167 displays potent anti-leukemic effects in chronic lymphocytic leukemia

et al. 2018

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TP53 pathway defects contributed to therapy resistance and adverse clinical outcome in chronic lymphocytic leukemia (CLL), which represents an unmet clinical need with few therapeutic options. Maternal embryonic leucine zipper kinase (MELK) is a novel oncogene, which plays crucial roles in mitotic progression and stem cell maintenance. OTSSP167, an orally administrated inhibitor targeting MELK, is currently in a phase I/II clinical trial in patients with advanced breast cancer and acute myeloid leukemia. Yet, no investigation has been elucidated to date regarding the oncogenic role of MELK and effects of OTSSP167 in chronic lymphocytic leukemia (CLL). Previous studies confirmed MELK inhibition abrogated cancer cell survival via p53 signaling pathway. Thus, we aimed to determine the biological function of MELK and therapeutic potential of OTSSP167 in CLL. Herein, MELK over-expression was observed in CLL cells, and correlated with higher WBC count, advanced stage, elevated LDH, increased β2-MG level, unmutated IGHV, positive ZAP-70, deletion of 17p13 and inferior prognosis of CLL patients. In accordance with functional enrichment analyses in gene expression profiling, CLL cells with depletion or inhibition of MELK exhibited impaired cell proliferation, enhanced fast-onset apoptosis, induced G2/M arrest, attenuated cell chemotaxis and promoted sensitivity to fludarabine and ibrutinib. However, gain-of-function assay showed increased cell proliferation and cell chemotaxis. In addition, OTSSP167 treatment reduced phosphorylation of AKT and ERK1/2. It decreased FoxM1 phosphorylation, expression of FoxM1, cyclin B1 and CDK1, while up-regulating p53 and p21 expression. Taken together, MELK served as a candidate of therapeutic target in CLL. OTSSP167 exhibits potent anti-tumor activities in CLL cells, highlighting a novel molecule-based strategy for leukemic interventions.

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Expression of Maternal Embryonic Leucine Zipper Kinase (MELK) Correlates to Malignant Potentials in Hepatocellular Carcinoma

Abstract: MELK expression in HCC is extremely intense compared to its expression reported in other types of cancer. MELK could be a promising effective tumor marker of HCC and further consideration is needed.

Cited by 17 publications

References 19 publications

Up-Regulated Maternal Embryonic Leucine Zipper Kinase Predicts Poor Prognosis of Hepatocellular Carcinoma Patients in a Chinese Han Population

Up-Regulated Maternal Embryonic Leucine Zipper Kinase Predicts Poor Prognosis of Hepatocellular Carcinoma Patients in a Chinese Han Population

Prognostic genes of hepatocellular carcinoma based on gene coexpression network analysis

Inhibition of maternal embryonic leucine zipper kinase with OTSSP167 displays potent anti-leukemic effects in chronic lymphocytic leukemia

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