A novel molecular cross-talk driving pancreatic cancer progression

一种驱动胰腺癌进展的新型分子串扰

• 批准号: 10335167
• 负责人: Ajay Pratap Singh
• 金额: $ 33.96万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10335167
• 关键词: Apoptosis; Automobile Driving; Back; Binding; CCNE1 gene; CRISPR/Cas technology; Cell Hypoxia; Cell Line; Cell Proliferation; Cell Survival; ChIP-seq; Clinical; Data; Dependence; Development; Disease stratification; Exhibits; Face; Genes; Genetic Engineering; Genetic Transcription; Genomics; Growth; HIF1A gene; Histologic; Human; Hypoxia; Incidence; Knock-out; Knowledge; Lead; Life Expectancy; Luciferases; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mediating; Mediator of activation protein; MicroRNAs; Molecular; Molecular Target; Neoplasm Metastasis; Null Lymphocytes; Pancreas; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Prevention; Preventive; Prognosis; Publishing; Quality of life; Regulation; Research; Resistance; Role; Sampling; Signal Pathway; Specificity; Stress; Stromal Neoplasm; Suggestion; System; TWIST1 gene; Testing; Therapeutic; Tissues; Up-Regulation; anticancer research; base; cancer diagnosis; clinically significant; gene network; improved; in silico; insight; mouse model; neoplastic cell; novel; novel strategies; nuclease; pancreatic cancer cells; pancreatic cancer patients; pancreatic neoplasm; promoter; response; transcriptional reprogramming; transcriptome; transcriptome sequencing; tumor; tumor hypoxia; tumor progression; v-myb Genes

Tumor cells inevitably face hypoxia during the course of their progression and their adaptation to hypoxic stress promotes invasive, metastatic and treatment-resistant phenotypes. Therefore, understanding the molecular basis underlying adaptive responses to hypoxia and identification of involved molecular targets will greatly facilitate the development of effective strategies for cancer management. We have recently provided first experimental evidence for a pathobiological role of MYB in pancreatic cancer (PC). Our novel preliminary findings now demonstrate i) role of MYB in hypoxic cell survival, ii), MYB-mediated regulation of HIF-1α, and iii) MYB-HIF-1α interaction and co-localization. In other novel findings, we show differential binding of MYB to its two target gene promoters under hypoxia. In addition, our novel data support the clinical significance of MYB by showing its wide-spread expression in pancreatic tumor cases, which is also suggestive of its association with increasing tumor-grade and patient's survival. Based on these compelling findings, we hypothesize that MYB-HIF1α crosstalk plays an important role in pancreatic cancer progression and metastasis, which will be tested in four specific aims. In aim 1, we will investigate the regulatory cross-talk between MYB and HIF-1α by studying coordinated regulation of MYB and HIF-1α under hypoxia, and any reciprocity that may exist between them. In aim 2, we will define the role of interaction between MYB and HIF-1α in their transcriptional reprogramming and hypoxia adaptive-response pathways. Specifically, we will examine if the MYB/HIF-1α crosstalk alters their genomic occupancy leading to changes in transcriptome, and characterize hypoxia adaptive-response phenotypes that are jointly or independently regulated by them. In aim 3, we will examine the cooperative functional significance of MYB and HIF-1α in pancreatic tumor progression and metastasis by using genetically-engineered, luciferase-tagged MYB- and HIF-1α expressing or knockout PC cells in an orthotopic mouse model. Histological and immunohistochemical studies will be performed to measure changes in tumor hypoxia, vasculature, cell proliferation/apoptosis, and metastasis. Finally, in aim 4, we will study the clinical significance of MYB-HIF-1α cross-talk in PC by performing immunohistochemical analysis in human pancreatic tumor samples along with adjacent and healthy normal pancreatic tissues to assess incidence, intensity and co-expression of MYB and HIF-1α. We will also examine their correlation (alone and in combination) with tumor -grade, -stage, and patient's survival. Together, these studies will deliver novel insight into the functional and mechanistic significance of a novel molecular cross-talk (MYB/HIF-1α) in PC pathobiology, and highlight its clinical significance. Resulting data would enhance our understanding of molecular pathogenesis of PC and, thus, facilitate the development of novel approaches for its prevention and treatment. Therefore, proposed studies have significant potential to impact pancreatic cancer research at various levels that will ultimately support effective management of this devastating malignancy.

肿瘤细胞在发展和适应缺氧的过程中不可避免地面临缺氧

项目成果

Mitochondrial fusion and fission: The fine-tune balance for cellular homeostasis.

• DOI: 10.1096/fj.202100067r
• 发表时间: 2021-06
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Adebayo M;Singh S;Singh AP;Dasgupta S
• 通讯作者: Dasgupta S

ETV4: an emerging target in pancreatic cancer.

• DOI: 10.18632/oncoscience.471
• 发表时间: 2018-09
• 期刊: Oncoscience
• 作者: Deshmukh SK;Singh AP;Singh S
• 通讯作者: Singh S

Biphasic transcriptional and posttranscriptional regulation of MYB by androgen signaling mediates its growth control in prostate cancer.

通过雄激素信号传导对MYB的双相转录和转录后调节介导了其在前列腺癌中的生长控制。

• DOI: 10.1016/j.jbc.2022.102725
• 发表时间: 2023-01
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Acharya, Srijan;Anand, Shashi;Khan, Mohammad Aslam;Zubair, Haseeb;Srivastava, Sanjeev Kumar;Singh, Seema;Singh, Ajay Pratap
• 通讯作者: Singh, Ajay Pratap

MYB exhibits racially disparate expression, clinicopathologic association, and predictive potential for biochemical recurrence in prostate cancer.

• DOI: 10.1016/j.isci.2023.108487
• 发表时间: 2023-12-15
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Khan, Mohammad Aslam;Acharya, Srijan;Anand, Shashi;Sameeta, Fnu;Pramanik, Paramahansa;Keel, Christopher;Singh, Seema;Carter, James Elliot;Dasgupta, Santanu;Singh, Ajay Pratap
• 通讯作者: Singh, Ajay Pratap

Detection of mitochondrial DNA mutations in circulating mitochondria-originated extracellular vesicles for potential diagnostic applications in pancreatic adenocarcinoma.

• DOI: 10.1038/s41598-022-22006-5
• 发表时间: 2022-11-02
• 期刊: Scientific reports
• 影响因子: 4.6