Details of a Researcher - Saya, Hideyuki

Papers - Saya, Hideyuki

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IGF1 receptor signaling regulates adaptive radioprotection in glioma stem cells

Osuka Satoru, Sampetrean Oltea, Shimizu Takatsune, Saga Isako, Onishi Nobuyuki, Sugihara Eiji, Okubo Jun, Fujita Satoshi, Takano Shingo, Matsumura Akira, Saya Hideyuki

Stem Cells 31 ( 4 ) 627 - 640 2013.04

ISSN 1066-5099

Cancer stem cells (CSCs) play an important role in disease recurrence after radiation treatment as a result of intrinsic properties such as high DNA repair capability and antioxidative capacity. It is unclear, however, how CSCs further adapt to escape the toxicity of the repeated irradiation regimens used in clinical practice. Here, we have exposed a population of murine glioma stem cells (GSCs) to fractionated radiation in order to investigate the associated adaptive changes, with the ultimate goal of identifying a targetable factor that regulates acquired radioresistance. We have shown that fractionated radiation induces an increase in IGF1 secretion and a gradual upregulation of the IGF type 1 receptor (IGF1R) in GSCs. Interestingly, IGF1R upregulation exerts a dual radioprotective effect. In the resting state, continuous IGF1 stimulation ultimately induces downregulation of Akt/ extracellular-signal-regulated kinases (ERK) and FoxO3a activation, which results in slower proliferation and enhanced self-renewal. In contrast, after acute radiation, the abundance of IGF1R and increased secretion of IGF1 promote a rapid shift from a latent state toward activation of Akt survival signaling, protecting GSCs from radiation toxicity. Treatment of tumors formed by the radioresistant GSCs with an IGF1R inhibitor resulted in a marked increase in radiosensitivity, suggesting that blockade of IGF1R signaling is an effective strategy to reverse radioresistance. Together, our results show that GSCs evade the damage of repeated radiation not only through innate properties but also through gradual inducement of resistance pathways and identify the dynamic regulation of GSCs by IGF1R signaling as a novel mechanism of adaptive radioprotection.

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XCT inhibition depletes CD44v-expressing tumor cells that are resistant to EGFR-targeted therapy in head and neck squamous cell carcinoma

Yoshikawa Momoko, Tsuchihashi Kenji, Ishimoto Takatsugu, Yae Toshifumi, Motohara Takeshi, Sugihara Eiji, Onishi Nobuyuki, Masuko Takashi, Yoshizawa Kunio, Kawashiri Shuichi, Mukai Makio, Asoda Seiji, Kawana Hiromasa, Nakagawa Taneaki, Saya Hideyuki, Nagano Osamu

Cancer Research 73 ( 6 ) 1855 - 1866 2013.03

ISSN 0008-5472

The targeting of antioxidant systems that allow stem-like cancer cells to avoid the adverse consequences of oxidative stress might be expected to improve the efficacy of cancer treatment. Here, we show that head and neck squamous cell carcinoma (HNSCC) cells that express variant isoforms of CD44 (CD44v) rely on the activity of the cystine transporter subunit xCT for control of their redox status. xCT inhibition selectively induces apoptosis in CD44v-expressing tumor cells without affecting CD44v-negative differentiated cells in the same tumor. In contrast to CD44v-expressing undifferentiated cells, CD44v-negative differentiated cells manifest EGF receptor (EGFR) activation and rely on EGFR activity for their survival. Combined treatment with inhibitors of xCT-dependent cystine transport and of EGFR resulted in a synergistic reduction of EGFR-expressing HNSCC tumor growth. Thus, xCT-targeted therapy may deplete CD44v-expressing undifferentiated HNSCC cells and concurrently sensitize the remaining differentiating cells to available treatments including EGFR-targeted therapy.

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Complexity of cancer stem cells

Sugihara Eiji, Saya Hideyuki

International Journal of Cancer 132 ( 6 ) 1249 - 1259 2013.03

ISSN 0020-7136

Heterogeneity of tumor tissue has been accounted for in recent years by a hierarchy-based model in which cancer stem cells (CSCs) have the ability both to self-renew and to give rise to differentiated tumor cells and are responsible for the overall organization of a tumor. Research into CSCs has progressed rapidly and concomitantly with recent advances in the biology of normal tissue stem cells, resulting in the identification of CSCs in a wide range of human tumors. Studies of mouse models of human cancer have provided further insight into the characteristics of CSCs as well as a basis for the development of novel therapies targeted to these cells. However, recent studies have revealed complexities, such as plasticity of stem cell properties and clonal diversity of CSCs, in certain tumor types that have led to revision of the original CSC model. In this review, we summarize the history of the discovery and characterization of CSCs, as well as address recent advances that have revealed the complexity of these cells and their therapeutic implications.

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Arf and p53 act as guardians of a quiescent cellular state by protecting against immortalization of cells with stable genomes

Osawa Tomoyuki, Atsumi Yuko, Sugihara Eiji, Saya Hideyuki, Kanno Masamoto, Tashiro Fumio, Masutani Mitsuko, Yoshioka Ken ichi

Biochemical and Biophysical Research Communications 432 ( 1 ) 34 - 39 2013.03

ISSN 0006-291X

Normal cells undergo a growth-arrested status that is produced by p53-dependent down-regulation of histone H2AX. Immortality is developed after abrogation of the H2AX-diminished state, which is associated with genomic instability (often with tetraploidy) and the induction of mutations in either the Arf or p53 gene. However, the role of Arf in control of H2AX expression and genome stability is still unclear. Here, we show that both Arf and p53 are required for the down-regulation of H2AX and formation of the growth-arrested state. Wild-type (WT) mouse embryonic fibroblasts (MEFs) subjected to tetraploidization with DNA lesions did not undergo mitotic catastrophe-associated cell death and stayed in a growth-arrested state, until immortality was attained with mutations in the Arf/. p53 module and recovery of H2AX expression. Whereas tetraploidization was essential for immortalization of WT MEFs, this event was not required for immortalization of MEFs containing mutations in Arf/. p53 and these cells still underwent mitotic catastrophe-associated cell death. Thus, WT MEFs are protected from immortalization with genome stability, which is abrogated with tetraploidization and mutation of either Arf or p53.

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Gene expression profile of a newly established choriocarcinoma cell line, iC³-1, compared to existing choriocarcinoma cell lines and normal placenta

Kobayashi Y., Banno K., Shimizu T., Ueki A., Tsuji K., Masuda K., Kisu I., Nomura H., Tominaga E., Nagano O., Saya H., Aoki D.

Placenta 34 ( 2 ) 110 - 118 2013.02

ISSN 0143-4004

Gestational choriocarcinoma is a malignant trophoblastic tumor that usually occurs in the uterus after pregnancy. The tumor is curable with advanced chemotherapy, but the molecular mechanism of choriocarcinoma tumorigenesis remains unclear. This is partly because the low incidence makes it difficult to obtain clinical samples for investigation and because an appropriate choriocarcinoma cell model to study the tumorigenesis has not been developed. We have established a new choriocarcinoma cell line, induced choriocarcinoma cell-1 (iC³-1), that possesses unique characteristics compared to other choriocarcinoma cell lines, including production of tumors that consist of the two types of cells commonly found in choriocarcinoma and mimicking of the clinical pathology. Existing trophoblast cell lines utilized in previous choriocarcinoma studies have had significantly dissimilar gene expression profiles. Therefore, it is important to choose an appropriate cell line for a particular study based on the characteristics of the cell line. In this study, to clarify the genetic characteristics of iC³-1 and to explore the tumorigenesis mechanism, we examined the gene profile of iC³-1 compared to those of existing cell lines and normal placental tissue. Bioinformatics analysis showed that several characteristic genes, IGF1R, CHFR, MUC3A, TAF7, PARK7, CDC123 and PSMD8, were significantly upregulated in iC ³-1 compared to BeWo and JEG3 cells. Interestingly, HAS2, CD44 and S100P were significantly upregulated in iC³-1 compared to parental HTR8/SVneo cells and normal third trimester placenta. Choriocarcinoma samples also showed immunoreactivity to HAS2, CD44 and S100. In summary, the gene expression profile of iC³-1 suggests that studies using this cell line can make an important contribution to improved understanding of choriocarcinoma tumorigenesis.

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Establishment of HRAS^G12V Transgenic Medaka as a Stable Tumor Model for In Vivo Screening of Anticancer Drugs

Matsuzaki Yuriko, Hosokai Haru, Mizuguchi Yukiyo, Fukamachi Shoji, Shimizu Atsushi, Saya Hideyuki

PLoS One 8 ( 1 ) 2013.01

Most targeted anticancer drugs have been identified by screening at the molecular or cellular level in vitro. However, many compounds selected by such costly and time-consuming screening do not prove effective against tumors in vivo. The development of anticancer drugs would thus be facilitated by the availability of an in vivo screening system based on a multicellular organism. We have now established a transgenic line of the freshwater fish medaka in which melanophores (melanocytes) proliferate in a manner dependent on heat shock-induced signaling by a human RAS oncoprotein. The human HRAS^G12V oncogene was expressed under the control of a melanophore-specific gene promoter in order to allow visualization of tumor growth in live fish maintained in a water tank. The expression of HRAS^G12V was induced as a result of Cre-mediated recombination by exposure of the fish to a temperature of 37°C for 30 min, given that the Cre gene was placed under the control of a medaka heat shock promoter. One of the stable transgenic lines developed abnormal pigment cell proliferation in the eyes and epidermis with 100% penetrance by 6 months postfertilization. Sorafenib, an inhibitor of RAS signaling, was administered to the transgenic fish and was found both to reduce the extent of melanophore proliferation and to improve survival. The transgenic medaka established here thus represents a promising in vivo system with which to screen potential anticancer drugs that target RAS signaling, and this system can readily be adapted for the screening of agents that target other oncogenes.

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The APC/C activator Cdh1 regulates the G2/M transition during differentiation of placental trophoblast stem cells

Naoe Hideaki, Chiyoda Tatsuyuki, Ishizawa Jo, Masuda Kenta, Saya Hideyuki, Kuninaka Shinji

Biochemical and Biophysical Research Communications 430 ( 2 ) 757 - 762 2013.01

ISSN 0006-291X

Differentiation of placental trophoblast stem (TS) cells to trophoblast giant (TG) cells is accompanied by transition from a mitotic cell cycle to an endocycle. Here, we report that Cdh1, a regulator of the anaphase-promoting complex/cyclosome (APC/C), negatively regulates mitotic entry upon the mitotic/endocycle transition. TS cells derived from homozygous Cdh1 gene-trapped (Cdh1^GT/GT) murine embryos accumulated mitotic cyclins and precociously entered mitosis after induction of TS cell differentiation, indicating that Cdh1 is required for the switch from mitosis to the endocycle. Furthermore, the Cdh1^GT/GT TS cells and placenta showed aberrant expression of placental differentiation markers. These data highlight an important role of Cdh1 in the G2/M transition during placental differentiation.

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Identification of novel small compounds that restore E-cadherin expression and inhibit tumor cell motility and invasiveness

Hirano Tamaki, Satow Reiko, Kato Asami, Tamura Mana, Murayama Yumi, Saya Hideyuki, Kojima Hirotatsu, Nagano Tetsuo, Okabe Takayoshi, Fukami Kiyoko

Biochemical Pharmacology 86 ( 10 ) 1419 - 1429 2013

ISSN 0006-2952

Tumor dissemination and invasive behavior are associated with a majority of cancer-related mortality cases. Loss of E-cadherin, which is caused by several tumor-promoting factors, is associated with metastasis and poor prognosis in many neoplasms. In this study, we aimed to identify small molecule compounds that restore the expression of E-cadherin, because these molecules are most likely to suppress tumor malignancy by restoring E-cadherin function and/or by inhibiting signals that suppress E-cadherin expression. Here, we developed a fluorescence screen system based on E-cadherin expression. A pilot drug library screen revealed that methotrexate (MTX) strongly induces E-cadherin expression in a colorectal cancer cell line, SW620. From the screen for 9600 compounds, we identified 9 hit compounds, which restored the expression of E-cadherin in SW620 and/or a melanoma cell line, SK-MEL-28. We confirmed that MTX and the other identified compounds transcriptionally promote E-cadherin expression. Among these, 2 compounds suppressed migration/invasion capacity in colorectal cancer cells and 3 in melanoma cells. A compound reduced SW620 migration and invasion with subtle effects on cell viability in SW620, SK-MEL-28, and a non-tumor cell line, HaCaT, with decrease in AKT and ERK1/2 protein levels. One of the other compounds reduced SK-MEL-28 cell migration and invasion and affected the viability only of SW620 and SK-MEL-28 cells but not HaCaT cells. These results suggest that these compounds would be attractive lead molecules as anti-metastasis agents.

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In vivo pH monitoring using boron doped diamond microelectrode and silver needles

Fierro Stéphane, Seishima Ryo, Nagano Osamu, Saya Hideyuki, Einaga Yasuaki

Scientific Reports 3 2013

This study presents the in vivo electrochemical monitoring of pH using boron doped diamond (BDD) microelectrode and silver needles for potential application in medical diagnosis. Accurate calibration curve for pH determination were obtained through in vitro electrochemical measurements. The increase induced in stomach pH by treatment with pantoprazole was used to demonstrate that it is possible to monitor the pH in vivo using the simple and noninvasive system proposed herein. Using the results of the in vivo and in vitro experiments, a quantitative analysis of the increase in stomach pH is also presented. It is proposed that the catheter-free pH monitoring system presented in this study could be potentially employed in any biological environment.

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Lysyl oxidase is induced by cell density-mediated cell cycle suppression via RB-E2F1-HIF-1α axis

Goto Takaaki M., Arima Yoshimi, Nagano Osamu, Saya Hideyuki

Cell Structure and Function 38 ( 1 ) 9 - 14 2013

ISSN 0386-7196

Remodeling of the matrix surrounding tumor cells plays a crucial role in the development and maintenance of cancer. Lysyl oxidase (LOX), a matrix remodeling factor, is induced by HIF-1α under hypoxic conditions and associated with tumor growth and metastasis. Here, we report that high cell density induces HIF-1α expression under normoxic condition, resulting in the promotion of LOX expression. This phenomenon was observed in the retinoblastoma tumor suppressor (RB)-proficient breast cancer cells but not in RB-deficient cells. In RB-proficient cancer cells, the cell cycle regulator E2F1 was down-regulated and cell cycle progression was inhibited at high density culture condition. Knockdown of E2F1 stabilized HIF-1α and promoted LOX expression, while knockdown of both E2F1 and HIF-1α prevented the up-regulation of LOX. These findings suggest that elevated cell density enhances cell cycle arrest and matrix remodeling via RB-E2F1-HIF-1α axis.

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A microfluidic invasion assay for glioma-initiating cells in three-dimensional culture

Fujioka Shingo, Oltea Sampetrean, Saya Hideyuki, Sudo Ryo

1075 - 1077 2013

This paper presents a microfluidic three-dimensional (3D) platform to investigate behaviors of glioma-initiating cells (GIC) cocultured with human umbilical vein endothelial cells (HUVEC). In this platform, these cells were cultured in microenvironments similar to in vivo. Especially, our experiments have been performed with GIC established by gene transfection [1], which is different from conventional tumor cell lines. Our results demonstrate that biochemical factors secreted by HUVEC attracts glioma invasion.

Reactive oxygen species-induced autophagic degradation of helicobacter pylori CagA is specifically suppressed in cancer stem-like cells

Tsugawa Hitoshi, Suzuki Hidekazu, Saya Hideyuki, Hatakeyama Masanori, Hirayama Toshiya, Hirata Kenro, Nagano Osamu, Matsuzaki Juntaro, Hibi Toshifumi

Cell Host and Microbe 12 ( 6 ) 764 - 777 2012.12

ISSN 1931-3128

Sustained expression of CagA, the type IV secretion effector of Helicobacter pylori, is closely associated with the development of gastric cancer. However, we observed that after translocation, CagA is degraded by autophagy and therefore short lived. Autophagy and CagA degradation are induced by the H. pylori vacuolating cytotoxin, VacA, which acted via decreasing intracellular glutathione (GSH) levels, causing reactive oxygen species (ROS) accumulation and Akt activation. Investigating this further, we found that CagA specifically accumulated in gastric cells expressing CD44, a cell-surface marker associated with cancer stem cells. The autophagic pathway in CD44-positive gastric cancer stem-like cells is suppressed because of their resistance to ROS, which is supported by increased intracellular GSH levels. These findings provide a molecular link between H. pylori and gastric carcinogenesis through the specific accumulation of CagA in gastric cancer stem-like cells.

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Tumor necrosis factor-α (TNF-α) stimulates the epithelial-mesenchymal transition regulator Snail in cholangiocarcinoma

Techasen Anchalee, Namwat Nisana, Loilome Watcharin, Bungkanjana Pornpan, Khuntikeo Narong, Puapairoj Anucha, Jearanaikoon Patcharee, Saya Hideyuki, Yongvanit Puangrat

Medical Oncology 29 ( 5 ) 3083 - 3091 2012.12

ISSN 1357-0560

Epithelial-mesenchymal transition (EMT) is a series of events during which epithelial cells lose many of their epithelial characteristics and take on properties that are typical of mesenchymal cells that lack cell-cell adhesion properties. EMT may be activated by various types of growth factors or inflammatory cytokines. In many types of epithelial cancers, the EMT-derived tumor cells are susceptible to metastasis. During tumor progression, epithelial cells acquire a gene expression pattern closely resembling that of mesenchymal cells. This study aimed to investigate the expression of the EMT-associated transcription factor Snail and an adhesion molecule E-cadherin in cholangiocarcinoma (CCA) tissues. The effect of TNF-α on EMT activation in CCA cells was also demonstrated. The qRT-PCR analysis revealed that Snail expression significantly increased in CCA (P = 0.01) and was correlated with tumor metastasis (P = 0.02). The expression of Snail was inversely associated with E-cadherin (P = 0.004). The stimulation of TNF-α enhances migration behavior and showed significantly induced expression of Snail in CCA cell lines, whereas expression of E-cadherin and CK-19 (the epithelial marker) was reduced. Immunofluorescence analysis revealed that TNF-α-treated CCA cell lines increased nuclear translocation of Snail, whereas E-cadherin was dramatically decreased. Our findings suggest that the changes in the expression of Snail or E-cadherin might regulate EMT development in CCA resulting in promoting tumor progression. Overexpression of Snail could be used as a prognostic marker for monitoring the treatment efficiency of CCA patients.

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Up-Regulation of Imp3 Confers In Vivo Tumorigenicity on Murine Osteosarcoma Cells

Ueki Arisa, Shimizu Takatsune, Masuda Kenta, Yamaguchi Sayaka I., Ishikawa Tomoki, Sugihara Eiji, Onishi Nobuyuki, Kuninaka Shinji, Miyoshi Keita, Muto Akihiro, Toyama Yoshiaki, Banno Kouji, Aoki Daisuke, Saya Hideyuki

PLoS One 7 ( 11 ) 2012.11

Osteosarcoma is a high-grade malignant bone tumor that manifests ingravescent clinical behavior. The intrinsic events that confer malignant properties on osteosarcoma cells have remained unclear, however. We previously established two lines of mouse osteosarcoma cells: AX cells, which are able to form tumors in syngeneic mice, and AXT cells, which were derived from such tumors and acquired an increased tumorigenic capacity during tumor development. We have now identified Igf2 mRNA-binding protein3 (Imp3) as a key molecule responsible for this increased tumorigenicity of AXT cells in vivo. Imp3 is consistently up-regulated in tumors formed by AX cells, and its expression in these cells was found to confer malignant properties such as anchorage-independent growth, loss of contact inhibition, and escape from anoikis in vitro. The expression level of Imp3 also appeared directly related to tumorigenic ability in vivo which is the critical determination for tumor-initiating cells. The effect of Imp3 on tumorigenicity of osteosarcoma cells did not appear to be mediated through Igf2-dependent mechanism. Our results implicate Imp3 as a key regulator of stem-like tumorigenic characteristics in osteosarcoma cells and as a potential therapeutic target for this malignancy.

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Reciprocal control of G ₁-phase progression is required for Th-POK/Runx3-mediated CD4/8 thymocyte cell fate decision

Sato Takehito, Chiba Tomoki, Ohno Shin Ichiro, Sato Chiharu, Sugoh Tatsuya, Miyashita Keiko, Akatsuka Hisako, Hozumi Katsuto, Okada Yoshinori, Iida Yumi, Akatsuka Akira, Agata Yasutoshi, Chiba Marin, Kohu Kazuyoshi, Satake Masanobu, Tanabe Hideyuki, Saya Hideyuki, Habu Sonoko

Journal of Immunology 189 ( 9 ) 4426 - 4436 2012.11

ISSN 0022-1767

After receiving a TCR-mediated differentiation signal, CD4 and CD8 double-positive thymocytes diverge into CD4 or CD8 single-positive T cells, for which Th-POK and Runx3 have been identified as pivotal transcription factors, respectively. The cross-antagonistic regulation of Th-POK and Runx3 seems to be essential for CD4/8 thymocyte lineage commitment. However, the process for determining which pivotal factor acts dominantly has not been established. To explore the determining process, we used an in vitro culture system in which CD4 or CD8 single-positive cells are selectively induced from CD4/8 double-positive cells. Surprisingly, we found that control of G ₁ cell cycle phase progression is critical for the determination. In the CD4 pathway, sustained TCR signal, as well as Th-POK, induces G ₁-phase extension and represses CD8 expression in a G ₁ extension-dependent manner. In the CD8 pathway, after receiving a transient TCR signal, the IL-7R signal, as well as Runx3, antagonizes TCR signal-mediated G ₁ extension and CD8 repression. Importantly, forced G ₁ extension cancels the functions of Runx3 to repress Th-POK and CD4 and to reactivate CD8. In contrast, it is suggested that forced G ₁ progression inhibits Th-POK function to repress CD8. Collectively, Th-POK and Runx3 are reciprocally involved in the control of G ₁-phase progression, on which they exert their functions dependently. These findings may provide novel insight into how CD4/CD8 cell lineages are determined by Th-POK and Runx3.

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Pyruvate kinase M2

Tamada Mayumi, Suematsu Makoto, Saya Hideyuki

Clinical Cancer Research 18 ( 20 ) 5554 - 5561 2012.10

ISSN 1078-0432

The M2 splice isoform of pyruvate kinase (PKM2), an enzyme that catalyzes the later step of glycolysis, is a key regulator of aerobic glycolysis (known as the Warburg effect) in cancer cells. Expression and low enzymatic activity of PKM2 confer on cancer cells the glycolytic phenotype, which promotes rapid energy production and flow of glycolytic intermediates into collateral pathways to synthesize nucleic acids, amino acids, and lipids without the accumulation of reactive oxygen species.PKM2 enzymatic activity has also been shown to be negatively regulated by the interaction with CD44 adhesion molecule, which is a cell surface marker for cancer stem cells. In addition to the glycolytic functions, nonglycolytic functions of PKM2 in cancer cells are of particular interest. PKM2 is induced translocation into the nucleus, where it activates transcription of various genes by interacting with and phosphorylating specific nuclear proteins, endowing cancer cells with a survival and growth advantage. Therefore, inhibitors and activators of PKM2 are well underway to evaluate their anticancer effects and suitability for use as novel therapeutic strategies.

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Novel strategies for cancer stem cells

Saya Hideyuki

International Journal of Biological Markers 27 ( 4 ) 2012.10

ISSN 0393-6155

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[Therapeutic strategy for breast cancer stem cells].

Yoshida G. J., Saya Hideyuki

Nihon rinsho. Japanese journal of clinical medicine 70 Suppl 7 243 - 248 2012.09

ISSN 0047-1852

CD44s regulates the TGF-β-mediated mesenchymal phenotype and is associated with poor prognosis in patients with hepatocellular carcinoma

Mima Kosuke, Okabe Hirohisa, Ishimoto Takatsugu, Hayashi Hiromitsu, Nakagawa Shigeki, Kuroki Hideyuki, Watanabe Masayuki, Beppu Toru, Tamada Mayumi, Nagano Osamu, Saya Hideyuki, Baba Hideo

Cancer Research 72 ( 13 ) 3414 - 3423 2012.07

ISSN 0008-5472

The prognosis for individuals diagnosed with hepatocellular carcinoma (HCC) remains poor because of the high frequency of invasive tumor growth, intrahepatic spread, and extrahepatic metastasis. Here, we investigated the role of the standard isoform of CD44 (CD44s), a major adhesion molecule of the extracellular matrix and a cancer stem cell marker, in the TGF-β-mediated mesenchymal phenotype of HCC. We found that CD44s was the dominant form of CD44 mRNA expressed in HCC cells. Overexpression of CD44s promoted tumor invasiveness and increased the expression of vimentin, a mesenchymal marker, in HCC cells. Loss of CD44s abrogated these changes. Also in the setting of CD44s overexpression, treatment with TGF-β1 induced the mesenchymal phenotype of HCC cells, which was characterized by low E-cadherin and high vimentin expression. Loss of CD44s inhibited TGF-β-mediated vimentin expression, mesenchymal spindle-like morphology, and tumor invasiveness. Clinically, overexpression of CD44s was associated with low expression of E-cadherin, high expression of vimentin, a high percentage of phospho-Smad2-positive nuclei, and poor prognosis in HCC patients, including reduced disease-free and overall survival. Together, our findings suggest that CD44s plays a critical role in the TGF-β-mediated mesenchymal phenotype and therefore represents a potential therapeutic target for HCC.

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Ink4a and Arf are crucial factors in the determination of the cell of origin and the therapeutic sensitivity of Myc-induced mouse lymphoid tumor

Sugihara E., Shimizu T., Kojima K., Onishi N., Kai K., Ishizawa J., Nagata K., Hashimoto N., Honda H., Kanno M., Miwa M., Okada S., Andreeff M., Saya H.

Oncogene 31 ( 23 ) 2849 - 2861 2012.06

ISSN 0950-9232

The cell of origin of tumors and the factors determining the cell of origin remain unclear. In this study, a mouse model of precursor B acute lymphoblastic leukemia/lymphoma (pre-B ALL/LBL) was established by retroviral transduction of Myc genes (N-Myc or c-Myc) into mouse bone marrow cells. Hematopoietic stem cells (HSCs) exhibited the highest susceptibility to N-Myc-induced pre-B ALL/LBL versus lymphoid progenitors, myeloid progenitors and committed progenitor B cells. N-Myc was able to induce pre-B ALL/LBL directly from progenitor B cells in the absence of Ink4a and Arf. Arf was expressed higher in progenitor B cells than Ink4a. In addition, N-Myc induced pre-B ALL/LBL from Arf/progenitor B cells suggesting that Arf has a predominant role in determining the cell of origin of pre-B ALL/LBL. Tumor cells derived from Ink4a/Arf/progenitor B cells exhibited a higher rate of proliferation and were more chemoresistant than those derived from wild-type HSCs. Furthermore, the Mdm2 inhibitor Nutlin-3 restored p53 and induced massive apoptosis in mouse pre-B ALL/LBL cells derived from Ink4a/Arf/cells and human B-ALL cell lines lacking Ink4a and Arf expression, suggesting that Mdm2 inhibition may be a novel therapeutic approach to the treatment of Ink4a/Arf/B-ALL/LBL, such as is frequently found in Ph ALL and relapsed ALL. Collectively, these findings indicate that Ink4a and Arf are critical determining factors of the cell of origin and the therapeutic sensitivity of Myc-induced lymphoid tumors.

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