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By taking advantage of forward genetic analysis in mice, we have demonstrated that Pak1 plays a crucial role during DMBA/TPA skin carcinogenesis. Although Pak1 has been considered to promote cancer development, its overall function remains poorly understood. To clarify the functional significance of Pak1 in detail, we sought to evaluate the possible effect of an allosteric inhibitor against PAK1 (NVS‐PAK1‐1) on a syngeneic mouse model. To this end, we established two cell lines, 9AS1 and 19AS1, derived from DMBA/TPA‐induced squamous cell carcinoma (SCC) that engrafted in FVB mice. Based on our present results, NVS‐PAK1‐1 treatment significantly inhibited the growth of tumors derived from 9AS1 and 19AS1 cells in vitro and in vivo. RNA‐sequencing analysis on the engrafted tumors indicates that NVS‐PAK1‐1 markedly potentiates the epidermal cell differentiation and enhances the immune response in the engrafted tumors. Consistent with these observations, we found an expansion of Pan‐keratin‐positive regions and potentially elevated infiltration of CD8‐positive immune cells in NVS‐PAK1‐1‐treated tumors as examined by immunohistochemical analyses. Together, our present findings strongly suggest that PAK1 is tightly linked to the development of SCC, and that its inhibition is a promising therapeutic strategy against SCC. PAK1 inhibitor treatment significantly inhibited the growth of tumors derived from 9AS1 and 19AS1 cells in vitro and in vivo.

Pak1 (serine/threonine p21-activated kinases) was previously reported to have oncogenic activity in several cancers. However, its roles in the cancer microenvironment are poorly understood. We demonstrated that Pak1 expression in Langerhans cells (LCs) is essential for the maintenance of epidermal stem cells and skin tumor development. We found that PAK1 is localized in LCs by immunohistochemistry. Furthermore, the number of LCs significantly decreased in MSM/Ms Pak1 homozygous knockout mice (MSM/Ms-Pak1-/-). F1 hybrid (FVB/N×MSM/Ms) Pak1 heterozygous knockout mice (F1-Pak1+/-) had increased numbers of Th17 cells in the skin. Therefore, Pak1 knockdown cells were prepared using LC-derived XS52 cells (XS52-Pak1KD) and co-cultured with keratinocyte-derived C5N cells. As a result, XS52-Pak1KD cell supernatants promoted C5N cell proliferation. We then carried out DMBA/TPA skin carcinogenesis experiments using F1-Pak1+/- mice. Of note, F1-Pak1+/- mice exhibited stronger resistance to skin tumors than control mice. F1-Pak1+/- mice had fewer epidermal stem cells in the skin bulge. Our study suggested that Pak1 regulates the epidermal stem cell number by changing the properties of LCs and functions in skin carcinogenesis. We clarified a novel role of Pak1 in regulating LCs as a potential therapeutic target in skin immune disease and carcinogenesis.

CENP‐50/U is a component of the CENP‐O complex (CENP‐O/P/Q/R/U) and localizes to the centromere throughout the cell cycle. Aberrant expression of CENP‐50/U has been reported in many types of cancers. However, as Cenp‐50/U‐deficient mice die during early embryogenesis, its functions remain poorly understood in vivo. To investigate the role of Cenp‐50/U in skin carcinogenesis, we generated Cenp‐50/U conditional knockout (K14CreER‐Cenp‐50/Ufl/fl) mice and subjected them to the 7,12‐dimethylbenz(a)anthracene (DMBA)/terephthalic acid (TPA) chemical carcinogenesis protocol. As a result, early‐stage papillomas decreased in Cenp‐50/U‐deficient mice. In contrast, Cenp‐50/U‐deficient mice demonstrated almost the same carcinoma incidence as control mice. Furthermore, mRNA expression analysis using DMBA/TPA‐induced papillomas and carcinomas revealed that Cenp‐50/U expression levels in papillomas were significantly higher than in carcinomas. These results suggest that Cenp‐50/U functions mainly in early papilloma development and it has little effect on malignant conversion. CENP‐50 is required for papilloma development, but has no function in malignant conversion.

MSM/Ms is a unique inbred mouse strain derived from the Japanese wild mouse, Mus musculus molossinus, which has been approximately 1 million years genetically distant from standard inbred mouse strains mainly derived from M. m. domesticus. Due to its genetic divergence, MSM/Ms has been broadly used in linkage studies. A bacterial artificial chromosome (BAC) library was constructed for the MSM/Ms genome, and sequence analysis of the MSM/Ms genome showed approximately 1% of nucleotides differed from those in the commonly used inbred mouse strain, C57BL/6J. Therefore, MSM/Ms mice are thought to be useful for functional genome studies. MSM/Ms mice show unique characteristics of phenotypes, including its smaller body size, resistance to high-fat-diet-induced diabetes, high locomotive activity, and resistance to age-onset hearing loss, inflammation, and tumorigenesis, which are distinct from those of common inbred mouse strains. Furthermore, ES (Embryonic Stem) cell lines established from MSM/Ms allow the MSM/Ms genome to be genetically manipulated. Therefore, genomic and phenotypic analyses of MSM/Ms reveal novel insights into gene functions that were previously not obtained from research on common laboratory strains. Tumorigenesis-related MSM/Ms-specific genetic traits have been intensively investigated in Japan. Furthermore, radiation-induced thymic lymphomas and chemically-induced skin tumors have been extensively examined using MSM/Ms.

CENP‐R is a component of the CENP‐O complex, including CENP‐O, CENP‐P, CENP‐Q, CENP‐R, and CENP‐U and is constitutively localized to kinetochores throughout the cell cycle in vertebrates. CENP‐R‐deficient chicken DT40 cells are viable and show a very minor effect on mitosis. To investigate the functional roles of CENP‐R in vivo, we generated CENP‐R‐deficient mice (Cenp‐r−/−). Mice heterozygous or homozygous for Cenp‐r null mutation are viable and healthy, with no apparent defect in growth and morphology, indicating Cenp‐r is not essential for normal development. Accordingly, to investigate the role of the Cenp‐r gene in skin carcinogenesis, we subjected Cenp‐r−/− mice to the 7,12‐dimethylbenz(a)anthracene (DMBA)/TPA chemical carcinogenesis protocol and monitored tumor development. As a result, Cenp‐r−/− mice initially developed significantly more papillomas than control wild‐type mice. However, papillomas in Cenp‐r−/− mice showed a decrease of proliferative cells and an increase of apoptotic cells. As a result, they did not grow bigger and some papillomas showed substantial regression. Furthermore, papillomas in Cenp‐r−/− mice showed lower frequency of malignant conversion to squamous cell carcinomas. These results indicate Cenp‐r functions bilaterally in cancer development: during early developmental stages, Cenp‐r functions as a tumor suppressor, but during the expansion and progression of papillomas it functions as a tumor‐promoting factor. Cenp‐r functions bilaterally in cancer development: during early developmental stages, Cenp‐r behaves as a tumor suppressor, but during the expansion and progression of papillomas it behaves as a tumor‐promoting factor.

Recent years have witnessed substantial progress in understanding tumor heterogeneity and the process of tumor progression; however, the entire process of the transition of tumors from a benign to metastatic state remains poorly understood. In the present study, we performed a prospective cancer genome-sequencing analysis by employing an experimental carcinogenesis mouse model of squamous cell carcinoma to systematically understand the evolutionary process of tumors. We surgically collected a part of a lesion of each tumor and followed the progression of these tumors in vivo over time. Comparative time-series analysis of the genomes of tumors with different fates, i.e., those that eventually metastasized and regressed, suggested that these tumors acquired and inherited different mutations. These findings suggest that despite the occurrence of an intra-tumor selection event for malignant alteration during the transformation from early- to late-stage papilloma, the fate determination of tumors might be determined at an even earlier stage.

High-throughput RNA sequencing technology is widely used to comprehensively detect and quantify cellular gene expression. Thus, numerous analytical methods have been proposed for identifying differentially expressed genes (DEGs) between paired samples such as tumor and control specimens, but few studies have reported methods for analyzing differential expression under multiple conditions. We propose a novel method, DEclust, for differential expression analysis among more than two matched samples from distinct tissues or conditions. As compared to conventional clustering methods, DEclust more accurately extracts statistically significant gene clusters from multi-conditional transcriptome data, particularly when replicates of quantitative experiments are available. DEclust can be used for any multi-conditional transcriptome data, as well as for extending any DEG detection tool for paired samples to multiple samples. Accordingly, DEclust can be used for a wide range of applications for transcriptome data analysis. DEclust is freely available at http://www.dna.bio.keio.ac.jp/software/DEclust.

Hair length in mammals is generally regulated by the hair cycle, and its disruption leads to abnormal hair morphogenesis in several species. FGF5, one of the hair cycle regulators, has a role in inducing catagen, and that mutation causes abnormal hair length in both sexes in humans, mice, dogs, and cats. Male-dominant long-haired coat (MALC) is an inbred strain of Syrian hamster exhibiting spontaneous long hair in males. After castration, MALC exhibited significantly shorter hair than the control individuals, but testosterone administration to castrated MALC showed reversion to the original phenotype. Moreover, flutamide administration led to MALC phenotype repression. Histological analysis revealed that hair follicle regression was shown in the wild-type 4 weeks after depilation, but that of MALC remained in the anagen phase. We detected a c.546delG of Fgf5 in MALC (Fgf5 ᵐᵃˡᶜ) that might lead to truncation resulting from a frame shift in FGF5 (p.Arg184GlyfsX6). Additionally, homozygous Fgf5 ᵐᵃˡᶜ was only detected in long-haired (Slc:Syrian × MALC)F₂ and (J-2-Nn × MALC)F₂ progenies, and all homozygous wild and heterozygous Fgf5 ᵐᵃˡᶜ individuals showed normal hair length. Thus, Fgf5 ᵐᵃˡᶜ leads to male-dominant long hair via a prolonged anagen phase which is affected by testosterone in hamsters. To our knowledge, this report is the first to present the sexual dimorphism of hair length caused by the Fgf5 mutation.

Radiation therapy is a useful treatment for tumors and vascular malformations of the central nervous system. Radiation therapy is associated with complications, including leukoencephalopathy, radiation necrosis, vasculopathy, and optic neuropathy. Secondary tumors are also often seen long after radiation therapy. Secondary tumors are often benign tumors, such as hemangiomas and meningiomas, but sometimes malignant gliomas and soft tissue sarcomas emerge. We review the imaging findings of complications that may occur after brain radiation therapy.

Mice of the C57BL/6 strain are resistant to the development of skin squamous carcinomas (SCCs) induced by an activated Ras oncogene, whereas FVB/N mice are highly susceptible 1 . The genetic basis of this difference in phenotype is unknown. Here we show that susceptibility to SCC is under the control of a carboxy-terminal polymorphism in the mouse Ptch gene. F 1 hybrids between C57BL/6 and FVB/N strains ((B6FVB)F 1 ) are resistant to Ras-induced SCCs, but resistance can be overcome either by elimination of the C57BL/6 Ptch allele ( Ptch B6 ) or by overexpression of the FVB/N Ptch allele ( Ptch FVB ) in the epidermis of K5Hras -transgenic (B6FVB)F 1 hybrid mice. The human Patched ( PTCH ) gene is a classical tumour suppressor gene for basal cell carcinomas and medulloblastomas, the loss of which causes increased signalling through the Sonic Hedgehog ( SHH ) pathway 2 , 3 , 4 , 5 . SCCs that develop in Ptch B6 +/- mice do not lose the wild-type Ptch gene or show evidence of increased SHH signalling. Although Ptch FVB overexpression can promote SCC formation, continued expression is not required for tumour maintenance, suggesting a role at an early stage of tumour cell lineage commitment. The Ptch polymorphism affects Hras-induced apoptosis, and binding to Tid1, the mouse homologue of the Drosophila l(2)tid tumour suppressor gene. We propose that Ptch occupies a critical niche in determining basal or squamous cell lineage, and that both tumour types can arise from the same target cell depending on carcinogen exposure and host genetic background.