Biology subjects

Nakayama, J.

Publications and source records attributed to Nakayama, J..

5 recordsLinked to original sources

bioRxiv2021

HSD11β1 promotes EMT-mediated breast cancer metastasis

Abnormal biosyntheses of steroid hormones and dysregulation of steroid hormone receptors contribute to breast cancer metastasis but the mechanisms of that are poorly understand. Here we report a stress hormone producing enzyme, Hydroxysteroid (11-Beta) Dehydrogenase 1 (HSD11{beta}1) promotes breast cancer metastasis. HSD11{beta}1 was ectopically expressed in seventy-one percent of triple-negative breast tumors and correlated with shorter overall survival. HSD11{beta}1 significantly promoted breast cancer metastasis through induction of epithelial-to-mesenchymal transition (EMT); conversely, pharmacologic and genetic inhibition of HSD11{beta}1 suppressed metastatic progression of breast cancer cells. Moreover, 11-hydroxyprogesterone (11-OHP) whom HSD11{beta}1 produced in breast cancer cells, conferred metastatic properties on non-metastatic breast cancer cells through induction of EMT. We identified Peroxisome Proliferator-activated Receptor Alpha (PPAR-) as essential for both HSD11{beta}1 and 11OHP-driven EMT. Knockdown of PPAR- induced MET on HSD11{beta}1-expressing breast cancer cells. Taken together, HSD11{beta}1 promotes breast cancer metastasis and would be a novel target for suppressing breast cancer metastasis.

cancer biology↗

bioRxiv2021

Aberrant accumulation of NIK promotes tumorigenicity by dysregulating post-translational modifications in breast cancer

Post-translational modifications and mRNA translation are frequently altered in human cancers. However, investigations to understand their roles in the cancer progression mechanism remain insufficient. In this research, we explored protein levels altered by translational or post-translational regulation by analyzing transcriptome and western blotting data of the highly malignant breast cancer cell lines. From these analyses, NIK was found to be upregulated at the protein level to predominantly activate the non-canonical NF-{kappa}B pathway in a breast cancer cell line. Furthermore, the increase in NIK protein production was attributed to the dysregulation of ubiquitin-proteasome system caused by a decrease in the translation of cIAP1. NIK upregulation contributed to tumorigenicity by regulating the expression of inflammatory response-related genes. Collectively, our study suggests that NIK is post-translationally modified and has the potential to be a therapeutic target and diagnostic marker for breast cancer.

cancer biology↗

bioRxiv2021

HOXB7 induces oncogenic transformation in NMuMG cells via JAK2-STAT3 signaling

The homeobox family genes are often dysregulated in a various cancer type. Particularly HOXB7 amplification and overexpression correlate with poor prognosis in various cancer such as gastric, pancreatic, and lung cancers. Moreover, HOXB7 is known to contribute to cancer progression by promoting epithelial to mesenchymal transition, anti-cancer drug resistance, and angiogenesis. In this study, we show that HOXB7 is coamplified with ERBB2 in a subset of breast cancer patients and HOXB7 expression correlates with poor prognosis in HER2-positive breast cancer patients. This clinical observation is supported by the following results: HOXB7 overexpression in an immortalized murine mammary gland epithelial cell line NMuMG induces cellular transformation in vitro, tumorigenesis and lung metastasis through the activation of JAK-STAT signaling.

cancer biology↗

bioRxiv2021

Cinnamon bark extract suppresses metastatic dissemination of cancer cells through inhibition of glycolytic metabolism

Metastasis, a leading contributor to the morbidity of cancer patients, occurs through multiple steps. As each of these steps is promoted by different molecular mechanisms, blocking metastasis needs to target each of these steps. Here we report that cinnamon bark extract (CBE) has a suppressor effect on metastatic dissemination of cancer cells. Though a zebrafish embryo screen which utilizes conserved mechanisms between metastasis and zebrafish gastrulation for identifying anti-metastasis drugs, CBE was identified to interfere with gastrulation progression of zebrafish. A zebrafish xenotransplantation model of metastasis validated that CBE suppressed metastatic dissemination of human cancer cells (MDA-MB-231). Interestingly, quantitative metabolome analyses revealed that CBE-treated MDA-MB-231 cells disrupted the production of glucose 6-phosphate (G6P) and fructose 6-phosphate (F6P), which are intermediate metabolites of glycolytic metabolism. CBE decreased the expression of hexokinase 2 (HK2), which catalyzes G6P production, and pharmacological inhibition of HK2 suppressed cell invasion and migration of MDA-MB-231 cells. Taken together, CBE suppressed metastatic dissemination of human cancer cells by inhibiting glycolytic metabolism.

pharmacology and toxicology↗

bioRxiv2021

Zebrafish embryo screen identifies anti-metastasis drugs

Metastasis is responsible for approximately 90% of cancer-associated mortality but few models exist that allow for rapid and effective screening of anti-metastasis drugs. Current mouse models of metastasis are too expensive and time consuming to use for rapid and high-throughput screening. Therefore, we created a unique screening concept utilizing conserved mechanisms between zebrafish gastrulation and cancer metastasis for identification of potential anti-metastatic drugs. We hypothesized that small chemicals that interrupt zebrafish gastrulation might also suppress metastatic progression of cancer cells and developed a phenotype-based chemical screen to test the hypothesis. The screen used epiboly, the first morphogenetic movement in gastrulation, as a marker and enabled 100 chemicals to be tested in five hours. The screen tested 1280 FDA-approved drugs and identified Pizotifen, an antagonist for serotonin receptor 2C (HTR2C) as an epiboly-interrupting drug. Pharmacologic and genetic inhibition of HTR2C suppressed metastatic progression in a mouse model. Blocking HTR2C with Pizotifen restored epithelial properties to metastatic cells through inhibition of Wnt-signaling. In contrast, HTR2C induced epithelial to mesenchymal transition (EMT) through activation of Wnt-signaling and promoted metastatic dissemination of human cancer cells in a zebrafish xenotransplantation model. Taken together, our concept offers a novel platform for discovery of anti-metastasis drugs.

cancer biology↗