Hiroshi Y . Yamada | University of Oklahoma Health Sciences Center (original) (raw)

Papers by Hiroshi Y . Yamada

bioRxiv (Cold Spring Harbor Laboratory), Apr 2, 2024

Colon cancer is the second most lethal cancer and is predicted to claim 49,700 lives in the Unite... more Colon cancer is the second most lethal cancer and is predicted to claim 49,700 lives in the United States this year. Chromosome instability (CIN) is observed in 80% to 90% of colon cancers and is thought to contribute to colon cancer progression and recurrence. To investigate the impact of CIN on colon cancer development, we developed shugoshin-1 (Sgo1) haploinsufficient (−/+) mice, an animal model focusing on mitotic error–induced CIN. In this study, we analyzed signature changes in the colonic transcriptome of Sgo1−/+ mice to examine the molecular events underlying the altered carcinogenesis profiles in Sgo1−/+ mice. We performed next-generation sequencing of normal-looking colonic mucosal tissue from mice treated with the carcinogen azoxymethane after 24 weeks. Transcriptome profiling revealed 349 hits with a 2-fold expression difference threshold (217 upregulated genes, 132 downregulated genes, P < 0.05). Pathway analyses indicated that the Sgo1-CIN tissues upregulated pathways known to be activated in colon cancer, including lipid metabolism (z score 4.47), Notch signaling (4.47), insulin signaling (3.81), and PPAR pathways (3.75), and downregulated pathways involved in immune responses including allograft rejection (6.69) and graft-versus-host disease (6.54). Notably, stem cell markers were also misregulated. Collectively, our findings demonstrate that systemic CIN results in transcriptomic changes in metabolism, proliferation, cell fate, and immune responses in the colon, which may foster a microenvironment amenable to cancer development. Therefore, therapeutic approaches focusing on these identified pathways may be valuable for colon cancer prevention and treatment. Cancer Res; 76(3); 630–42. ©2016 AACR.

List of 349 differentially expressed genes in normal-looking colonic mucosal tissues in Sgo1, com... more List of 349 differentially expressed genes in normal-looking colonic mucosal tissues in Sgo1, compared with control wild type. (P<0.05, 2-fold cutoff)

npj Precision Oncology

In the US, the majority of cancer samples analyzed are from white people, leading to biases in ra... more In the US, the majority of cancer samples analyzed are from white people, leading to biases in racial and ethnic treatment outcomes. Colorectal cancer (CRC) incidence and mortality rates are high in Alabama African Americans (AAs) and Oklahoma American Indians (AIs). We hypothesized that differences between racial groups may partially explain these disparities. Thus, we compared transcriptomic profiles of CRCs of Alabama AAs, Oklahoma AIs, and white people from both states. Compared to CRCs of white people, CRCs of AAs showed (a) higher expression of cytokines and vesicle trafficking toward modulated antitumor-immune activity, and (b) lower expression of the ID1/BMP/SMAD axis, IL22RA1, APOBEC3, and Mucins; and AIs had (c) higher expression of PTGS2/COX2 (an NSAID target/pro-oncogenic inflammation) and splicing regulators, and (d) lower tumor suppressor activities (e.g., TOB2, PCGF2, BAP1). Therefore, targeting strategies designed for white CRC patients may be less effective for AAs/...

Journal of Cell Science, 2000

Selective proteolysis at and after the onset of anaphase is a key cell cycle event required for s... more Selective proteolysis at and after the onset of anaphase is a key cell cycle event required for sister chromatid separation as well as for exit from mitosis. It requires ubiquitination of substrates by Anaphase Promoting Complex(APC)/ Cyclosome. Slp1, a WD-repeat protein, is a putative activator for APC in fission yeast. With another WD-repeat protein, Ste9/Srw1, it is thought to promote the proteolysis in a substrate-specific manner. We report here characterization of a temperature-sensitive (ts) slp1 mutant and its high-dosage suppressor, grt1+. In cells arrested in metaphase, wild-type Slp1 was preferentially found in a complex with hyperphosphorylated Cut9 (subunit of APC), whereas the ts Slp1 protein, lacking the last 113 amino acids, failed to interact with Cut9. The temperature sensitivity was suppressed by high dosage expression of a zinc finger protein, Grt1. The ts slp1 mutant was unable to maintain the normal level of Grt1 protein. The reduction in the Grt1 level may be a...

Cancer Prevention Research

The Pancreatic Cancer Early Detection (PRECEDE) Consortium was launched internationally to assess... more The Pancreatic Cancer Early Detection (PRECEDE) Consortium was launched internationally to assess the surveillance of high-risk individuals (HRI) of pancreatic cancer, focusing on genetic risk factors. In the early recruitment period of 3 years from May 2020 to March 2022, the PRECEDE gathered analysis-eligible data on 1,113 HRIs. In this issue of Cancer Prevention Research, Katona and colleagues reported current portrait of demographics of the participants, with significant disparities in gender, race and ethnicity. Now the PRECEDE Consortium aims at correcting these disparities in the next 3 years and double the percentage of underrepresented groups to more closely represent the demographics of patients. See related article by Katona et al., p. 343

Cancer Research

Background: Colorectal cancers (CRCs) is the third most commonly diagnosed cancer and the second ... more Background: Colorectal cancers (CRCs) is the third most commonly diagnosed cancer and the second most lethal cancer worldwide. CRCs carry high degrees of genomic instability (GI), which enables cancer evolution and makes prognosis poorer. Thus, GI is an exploitable target for therapy purposes. GI can be caused by gene mutation, alteration in gene expression, epigenetic modification, and other infectious or environmental factors. Several mutated genes involved in Chromosome instability and/or microsatellite instability have been identified. Yet it has not been technically feasible to modify functions of mutated genes (e.g., APC, TP53). From the drug development’ standpoint, inhibition of over-expressed target gene is preferred. However, specific genes involved in GI via expression alterations in CRCs have not been comprehensively identified. The gap in knowledge hinders development of CRC therapies targeting GI in CRC. In a previous study, we developed a data mining strategy (Gene Ex...

Neural Regeneration Research, 2021

Aging Cell, 2020

The cerebral amyloid‐β accumulation that begins in middle age is considered the critical triggeri... more The cerebral amyloid‐β accumulation that begins in middle age is considered the critical triggering event in the pathogenesis of late‐onset Alzheimer's disease (LOAD). However, the molecular mechanism remains elusive. The Shugoshin 1 (Sgo1−/+) mouse model, a model for mitotic cohesinopathy‐genomic instability that is observed in human AD at a higher rate, showed spontaneous accumulation of amyloid‐β in the brain at old age. With the model, novel insights into the molecular mechanism of LOAD development are anticipated. In this study, the initial appearance of cerebral amyloid‐β accumulation was determined as 15‐18 months of age (late middle age) in the Sgo1−/+ model. The amyloid‐β accumulation was associated with unexpected GSK3α/β inactivation, Wnt signaling activation, and ARC/Arg3.1 accumulation, suggesting involvement of both the GSK3‐Arc/Arg3.1 axis and the GSK3‐Wnt axis. As observed in human AD brains, neuroinflammation with IFN‐γ expression occurred with amyloid‐β accumulation and was pronounced in the aged (24‐month‐old) Sgo1−/+ model mice. AD‐relevant protein panels (oxidative stress defense, mitochondrial energy metabolism, and β‐oxidation and peroxisome) analysis indicated (a) early increases in Pdk1 and Phb in middle‐aged Sgo1−/+ brains, and (b) misregulations in 32 proteins among 130 proteins tested in old age. Thus, initial amyloid‐β accumulation in the Sgo1−/+ model is suggested to be triggered by GSK3 inactivation and the resulting Wnt activation and ARC/Arg3.1 accumulation. The model displayed characteristics and affected pathways similar to those of human LOAD including neuroinflammation, demonstrating its potential as a study tool for the LOAD development mechanism and for preclinical AD drug research and development.

Molecular carcinogenesis, Mar 1, 2017

Aneuploidy was predicted to cause cancer. To test the prediction, various Chromosome Instability ... more Aneuploidy was predicted to cause cancer. To test the prediction, various Chromosome Instability (CIN) mice models that carry transgenic mutations in mitotic regulators have been created. The availability of these mice has aided researchers in discovering connections between CIN, cancer, and aging. This review will focus on recent interdisciplinary findings regarding how CIN and aneuploidy affect carcinogenesis, immune dysfunction, and aging. High CIN can be generated in vivo by various intrinsic alterations (e.g., gene mutation, epigenetic modification) and extrinsic/environmental challenges (e.g., biological, chemical, biophysical), while immune surveillance, cell death, and natural turnover can remove cells with CIN. CIN itself is mutagenic and may cause further cellular mutations, which can be carcinogenic. Mitotically damaged cells can activate senescence-related tumor suppressors (e.g., p21(WAF1) , p27(KIP1) , p16(INK4A) ), which may lead to tissue-level senescence/aging throu...

Carcinogenesis, 2017

The incidence of liver cancer has increased in recent years. Worldwide, liver cancer is common: m... more The incidence of liver cancer has increased in recent years. Worldwide, liver cancer is common: more than 600000 related deaths are estimated each year. In the USA, about 27170 deaths due to liver cancer are estimated for 2016. Liver cancer is highly resistant to conventional chemotherapy and radiotherapy. For all stages combined, the 5-year survival rate is 15-17%, leaving much to be desired for liver cancer prevention and therapy. Heterogeneity, which can originate from genomic instability, is one reason for poor outcome. About 80-90% of liver cancers are hepatocellular carcinoma (HCC), and recent cancer genome sequencing studies have revealed frequently mutated genes in HCC. In this review, we discuss the cause of the tumor heterogeneity based on the functions of genes that are frequently mutated in HCC. We overview the functions of the genes that are most frequently mutated (e.g. TP53, CTNNB1, AXIN1, ARID1A and WWP1) that portray major pathways leading to HCC and identify the ro...

Cancer Research, 2015

(a) Colon cancer is the second most lethal cancer and is predicted to claim 50,310 lives in 2014.... more (a) Colon cancer is the second most lethal cancer and is predicted to claim 50,310 lives in 2014. Chromosome Instability (CIN) is observed in 80-90% of colon cancers and is thought to contribute to colon cancer progression and recurrence. We developed animal models focusing on mitotic error-induced CIN, Shugoshin-1 (Sgo1) haploinsufficient (-/+) mice, to investigate the impact of CIN on colon cancer development. Sgo1-/+ mice showed altered profiles in colonic lesions and cancer development. In this study, we analyzed signature changes in the colonic transcriptome of Sgo1-/+ mice to investigate underlying molecular events in the altered carcinogenesis profiles. (b) We treated control and Sgo1-/+ mice with colonic carcinogen azoxymethane (AOM), and tracked colon cancer development 12, 24, and 36 weeks after AOM treatments. We performed Next Generation Sequencing (NGS)-based transcriptome analysis at 24 weeks. (c) There were 349 hits with 2-fold expression difference threshold, P<0.05 (217 upregulated genes, 132 downregulated genes). In normal-looking colonic mucosal tissue from Sgo1 mice, we observed notable transcriptomic changes in the lipid metabolism, Notch signaling, insulin signaling, and peroxisome proliferator-activated receptor (PPAR) pathways. The profile had partial overlap with the colon tumor transcriptome, consistent with high prevalence of CIN in colon cancer. By applying secondary selection criteria, we also identified cell surface markers that may be used to selectively target colonic CIN cells with antibody-based or vaccine approaches. (d) Systemic Chromosome Instability resulted in transcriptomic changes in metabolic and proliferation regulators in the colon. We propose that the CIN effect may be countered through manipulation of these pathways. Citation Format: Chinthalapally V. Rao, Saira Sanghera, Yuting Zhang, Laura Biddick, Arun Reddy, Stan Lightfoot, Altaf Mohammed, Wei Dai, Hiroshi Y. Yamada. Systemic Chromosome Instability (CIN) resulted in transcriptomic changes in metabolic and proliferation regulators in colonic mucosal tissue of Sgo1-/+ mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2881. doi:10.1158/1538-7445.AM2015-2881

Cancer Research, 2014

(a) Colon cancer is the second most lethal cancer and is predicted to claim 50,830 lives in 2013.... more (a) Colon cancer is the second most lethal cancer and is predicted to claim 50,830 lives in 2013. Chromosome Instability (CIN) is observed in 80-90% of colon cancers and is thought to contribute to colon cancer progression and recurrence. For drug development, animal models that reflect cancer-specific etiology is necessary. However, animal models focusing on CIN have not been validated for colon cancer development and for drug testing. In this study, we set out to validate a mitotic error-induced CIN model mice, Shugoshin1 (Sgo1) haploinsufficient mice, as a colon cancer study model. (b) We treated control and Sgo1-/+ mice with colonic carcinogen Azoxymethane (AOM), and tracked colon cancer development over 12, 24 and 36 weeks after AOM treatments. The three endpoints provided information regarding the time course for colon cancer development. (c) Although we predicted an increase in colon tumors in Sgo1-/+ mice at a later (24 or 36 weeks) endpoint, precancerous lesions the Aberrant Crypt Foci (ACF) did not develop to larger tumors straightforwardly. Unexpectedly, the numbers of gross colon tumors showed no difference (P>0.05). Immunohistological analyses indicated IL6, Bcl2 and p16INK4A were differentially expressed in Sgo1-/+ mice. (d) We propose that formation of ACF in Sgo1-/+ mice are facilitated by IL6-STAT3-SOCS3 oncogenic pathway and Bcl2-anti-apoptotic pathway, yet further development of the ACF to tumors are inhibited by p16INK4A tumor suppressor pathway. Manipulating these pathways would be beneficial for inhibiting development of colon cancer with CIN. The CIN mice may be useful for investigating carcinogenesis in earlier stage and tumor regression in later stage. Citation Format: Chinthalapally V. Rao, Saira Sanghera, Yuting Zhang, Laura Biddick, Stan Lightfoot, Wei Dai, Hiroshi Y. Yamada. Antagonizing pathways leading to differential dynamics in colonic carcinogenesis in azoxymethane (AOM)-treated Sgo1 (Shugoshin1)-haploinsufficient chromosome instability (CIN) model mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 93. doi:10.1158/1538-7445.AM2014-93

Cancer Research, 2013

Mitotic errors have been suspected to be a cause of aneuploidy, rapid accumulation of mutations, ... more Mitotic errors have been suspected to be a cause of aneuploidy, rapid accumulation of mutations, and tumorigenesis. In addition, recent cell biological studies demonstrated that mitotic errors can result in DNA damage, which would also aid accumulation of mutations then carcinogenesis. However, no observations in vivo have been provided to support the cell biological observations to date. Previously we developed two strains of high Chromosome Instability (CIN) model mice, which show an increase in mitotic errors due to haploinsufficiency in chromosome cohesion system component Sgo1 or mitotic spindle checkpoint component BubR1. The pathways affected by these mutations are suggested to play a role in aging and carcinogenesis in human. Consistently, compared with wild type, both mice strains showed a significant risk for tumor development in colon with chemical carcinogenesis assays. In this study, we used these CIN mice to test whether (i) spontaneous carcinogenesis occurs in the mic...

Current Drug Targets, 2012

Current Cancer Drug Targets, 2010

Spindle poisons/anti-microtubule drugs are established chemotherapy drugs. These drugs primarily ... more Spindle poisons/anti-microtubule drugs are established chemotherapy drugs. These drugs primarily target microtubules and mitotic spindles, activate spindle assembly checkpoint (SAC), resulting in caspase-mediated cell death. However, the terminal phenotypes of drug-treated cells are surprisingly heterogeneous ranging from mitotic catastrophe to apparent senescence, suggesting that input from a variety of signaling pathways influence the cell death process. In recent years, studies revealed several signaling pathways that modulate the efficacy of spindle poisons. In this review, we discuss the genes and pathways whose inhibition or overexpression modulates spindle poison sensitivity. These genes cluster to (i) microtubule, microtubule associating proteins (MAPS) and actin cytoskeleton regulators, (ii) the SAC components, (iii) signaling proteins, (iv) chaperones, (v) cell cycle regulators, (vi) proteasome components, (vii) transcription factors and nuclear receptors, and (viii) apoptotic factors. These gene products would be potential targets for drugs to be combined with spindle poisons. Expression status of these genes would also serve as a prognostic marker for spindle poison-mediated chemotherapy. Understanding signaling pathways involved in drug efficacy will aid to rationally develop synergistic chemotherapy strategy.

Cancer Research, 2011

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Inactivation of Shugoshi... more Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Inactivation of Shugoshin-1 (Sgo1) function or depletion of Sgo1 in mammalian cells causes missegregation of chromosome. Sgo1 plays an obligate role in chromosome cohesion and its defect is implicated in high chromosome instability. Recent studies indicate that Sgo1 levels were significantly decreased in human colonic tumors, suggesting a role in colon carcinogenesis. Here, we report for first time that depletion of Sgo1 lead to the enhanced colorectal carcinogenesis in mice. To understand the role of Sgo1 in colorectal cancer, we have established haploinsufficient Sgo1+/- mouse model. We tested whether Sgo1 deficiency would enhance the colon carcinogenesis in animal exposed to colonic specific carcinogen. At eight weeks of age mice Sgo1+/+ and Sgo1+/- were treated with azoxymethane (AOM), s.c., 4 mg/kg BW, twice weekly for four weeks. Upon treatment with AOM, we analyzed for colonic crypt cell-cycle modifications and later stage colonic ACF and tumor formation. Sgo1-/+ mice showed higher acute cell death rate than Sgo1+/+ mice soon after the AOM-treatment. However, at the endpoint, the number of aberrant crypt foci [Sgo1+/+, 4±1.41 vs Sgo1+/- 12.2 ±1.5, mean ±SD, p<0.0002] and multiplicity of aberrant crypts/foci [Sgo1+/+ 0.4±0.32 vs Sgo1+/- 3.8 ±0.57, mean ±SD, p<0.0001]. Importantly, mean number of colonic microadenoma were 5-fold higher in haploinsufficient mice [Sgo1+/+, 0.8 ±0.45 vs Sgo1+/- 5.0 ± 1.2, p<0001]. Normal-looking colonic mucosa in AOM-treated Sgo1-/+ mice expressed higher Bcl2, p53 and COX-2 proteins compared with Sgo1+/+ type. These results suggest the notion that defect in mitotic machinery can serve both oncogenic and enhance cell death by apoptosis in an environment-dependent manner; Sgo1-/+ mice may be latently antagonizing carcinogenesis by removing damaged cells in higher rate with cell death. Our results for the first time provide functional evidence of Sgo1 in enhancement of precancerous lesions, and their progression to colonic tumors. (Supported by R01-CA-113349 and R01-CA-102942) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2983. doi:10.1158/1538-7445.AM2011-2983