Functional and Clinicopathological Analysis of Loss of MKK4 Expression in Endometrial Cancer

Ishikawa, Masatoshi; Nakayama, Kentaro; Rahman, Mohammed Tanjimur; Rahman, Munmun; Katagiri, Atsuko; Iida, Kouji; Miyazaki, Kohji

doi:10.1159/000322644

Cited by 12 publications

(10 citation statements)

References 24 publications

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“…MKK4 expression was previously shown to be reduced during cancer progression in prostate and ovary carcinomas [31,32]. Similar results were shown in other epithelial cancers, including endometrial carcinoma, gastric carcinoma, and pancreatic cancer [33][34][35]. MKK4 is generally accepted to be a metastasis suppressor, but there are still conflicting reports in the literature.…”

Section: Discussionsupporting

confidence: 62%

Metastasis suppressor proteins in cutaneous squamous cell carcinoma

Bozdoğan

Vargel

Çavuşoğlu

et al. 2016

Pathology - Research and Practice

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Cutaneous squamous cell carcinomas (cSCCs) are common human carcinomas. Despite having metastasizing capacities, they usually show less aggressive progression compared to squamous cell carcinoma (SCC) of other organs. Metastasis suppressor proteins (MSPs) are a group of proteins that control and slow-down the metastatic process. In this study, we established the importance of seven well-defined MSPs including NDRG1, NM23-H1, RhoGDI2, E-cadherin, CD82/KAI1, MKK4, and AKAP12 in cSCCs. Protein expression levels of the selected MSPs were detected in 32 cSCCs, 6 in situ SCCs, and two skin cell lines (HaCaT, A-431) by immunohistochemistry. The results were evaluated semi-quantitatively using the HSCORE system. In addition, mRNA expression levels were detected by qRT-PCR in the cell lines. The HSCOREs of NM23-H1 were similar in cSCCs and normal skin tissues, while RGHOGDI2, E-cadherin and AKAP12 were significantly downregulated in cSCCs compared to normal skin. The levels of MKK4, NDRG1 and CD82 were partially conserved in cSCCs. In stage I SCCs, nuclear staining of NM23-H1 (NM23-H1nuc) was significantly lower than in stage II/III SCCs. Only nuclear staining of MKK4 (MKK4nuc) showed significantly higher scores in in situ carcinomas compared to invasive SCCs. In conclusion, similar to other human tumors, we have demonstrated complex differential expression patterns for the MSPs in in-situ and invasive cSCCs. This complex MSP signature warrants further biological and experimental pathway research.

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Section: Discussionsupporting

confidence: 62%

Metastasis suppressor proteins in cutaneous squamous cell carcinoma

Bozdoğan

Vargel

Çavuşoğlu

et al. 2016

Pathology - Research and Practice

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“…Therefore despite genistein's inhibition of human PCa metastasis, the role of MAP2K4 in regulating metastasis formation cannot be determined from these findings. The uncertainty of MAP2K4's role in regulating human prostate cancer metastasis is further increased by studies across several different cancer types which support either a metastasis suppressor [6], [7], [19]–[21], or stimulatory role [9], [11], [17], [18]. Importantly, none have examined MAP2K4's role in regulating metastatic behavior of human PCa.…”

Section: Introductionmentioning

confidence: 99%

Mitogen-Activated Protein Kinase Kinase 4 (MAP2K4) Promotes Human Prostate Cancer Metastasis

et al. 2014

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Prostate cancer (PCa) is the second leading cause of cancer death in the US. Death from PCa primarily results from metastasis. Mitogen-activated protein kinase kinase 4 (MAP2K4) is overexpressed in invasive PCa lesions in humans, and can be inhibited by small molecule therapeutics that demonstrate favorable activity in phase II studies. However, MAP2K4's role in regulating metastatic behavior is controversial and unknown. To investigate, we engineered human PCa cell lines which overexpress either wild type or constitutive active MAP2K4. Orthotopic implantation into mice demonstrated MAP2K4 increases formation of distant metastasis. Constitutive active MAP2K4, though not wild type, increases tumor size and circulating tumor cells in the blood and bone marrow. Complementary in vitro studies establish stable MAP2K4 overexpression promotes cell invasion, but does not affect cell growth or migration. MAP2K4 overexpression increases the expression of heat shock protein 27 (HSP27) protein and protease production, with the largest effect upon matrix metalloproteinase 2 (MMP-2), both in vitro and in mouse tumor samples. Further, MAP2K4-mediated increases in cell invasion are dependent upon heat shock protein 27 (HSP27) and MMP-2, but not upon MAP2K4's immediate downstream targets, p38 MAPK or JNK. We demonstrate that MAP2K4 increases human PCa metastasis, and prolonged over expression induces long term changes in cell signaling pathways leading to independence from p38 MAPK and JNK. These findings provide a mechanistic explanation for human studies linking increases in HSP27 and MMP-2 to progression to metastatic disease. MAP2K4 is validated as an important therapeutic target for inhibiting human PCa metastasis.

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“…A large body of evidence has indicated that MAP2K4 is aberrantly expressed in numerous tumours, such as osteosarcoma (36), tongue squamous cell carcinoma (37), breast cancer (38) and pancreatic cancer (39). MAP2K4 is involved in various pathophysiological processes of tumourigenesis and tumour development, including cell proliferation, cycle, apoptosis, invasion and metastasis (36,(39)(40)(41). In PCa, MAP2K4 is overexpressed in tumour tissues.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‑136 inhibits prostate cancer cell proliferation and invasion by directly targeting mitogen‑activated protein kinase kinase 4

et al. 2018

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Prostate cancer (PCa) is the second most common type of cancer and the 6th leading cause of cancer‑associated mortality worldwide. Accumulated evidence suggests that PCa initiation and progression are controlled by microRNAs (miRNAs). Therefore, investigating PCa‑associated miRNAs may provide novel biomarkers for the diagnosis and treatment of patients with PCa. In the present study it was demonstrated that miRNA‑136 (miR‑136) expression was significantly downregulated in PCa tissues and cell lines. The resumption of miR‑136 expression suppressed cell proliferation and invasion in PCa cells. Bioinformatics analysis predicted that mitogen‑activated protein kinase kinase 4 (MAP2K4) was a direct target of miR‑136. This prediction was experimentally confirmed by a luciferase reporter assay, RT‑qPCR and western blot analysis. MAP2K4 was highly expressed in PCa tissues and inversely correlated with the miR‑136 expression level. Additionally, the restoration of MAP2K4 expression significantly blocked the inhibitory effects of miR‑136 on cell proliferation and invasion in PCa cells. Therefore, miR‑136 may suppress the proliferation and invasion of PCa cells by targeting MAP2K4 and may be a novel candidate target for cancer therapy against PCa.

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Functional and Clinicopathological Analysis of Loss of MKK4 Expression in Endometrial Cancer

Cited by 12 publications

References 24 publications

Metastasis suppressor proteins in cutaneous squamous cell carcinoma

Metastasis suppressor proteins in cutaneous squamous cell carcinoma

Mitogen-Activated Protein Kinase Kinase 4 (MAP2K4) Promotes Human Prostate Cancer Metastasis

MicroRNA‑136 inhibits prostate cancer cell proliferation and invasion by directly targeting mitogen‑activated protein kinase kinase 4

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