Oncology Commons^™

Upregulation Of Cd36, A Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis By Increasing Mmp28 And Decreasing E-Cadherin Expression, James Drury, Piotr G. Rychahou, Courtney O. Kelson, Mariah E. Geisen, Yuanyuan Wu, Daheng He, Chi Wang, Eun Y. Lee, B. Mark Evers, Yekaterina Y. Zaytseva

Surgery Faculty Publications

Altered fatty acid metabolism continues to be an attractive target for therapeutic intervention in cancer. We previously found that colorectal cancer (CRC) cells with a higher metastatic potential express a higher level of fatty acid translocase (CD36). However, the role of CD36 in CRC metastasis has not been studied. Here, we demonstrate that high expression of CD36 promotes invasion of CRC cells. Consistently, CD36 promoted lung metastasis in the tail vein model and GI metastasis in the cecum injection model. RNA-Seq analysis of CRC cells with altered expression of CD36 revealed an association between high expression of CD36 and upregulation …

Neurotensin Regulates Proliferation And Stem Cell Function In The Small Intestine In A Nutrient-Dependent Manner, Stephanie A. Rock, Kai Jiang, Yuanyuan Wu, Yajuan Liu, Jing Li, Heidi L. Weiss, Chi Wang, Jianhang Jia, Tianyan Gao, B. Mark Evers

Surgery Faculty Publications

BACKGROUND & AIMS: Intestinal stem cells (ISCs) are sensitive to dietary alterations and nutrient availability. Neurotensin (NT), a gut peptide localized predominantly to the small bowel and released by fat ingestion, stimulates the growth of intestinal mucosa under basal conditions and during periods of nutrient deprivation, suggesting a possible role for NT on ISC function.

METHODS: Leucine-rich repeat-containing G-protein coupled receptor 5-Enhanced Green Fluorescent Protein (Lgr5-EGFP) NT wild type (Nt^+/+) and Lgr5-EGFP NT knockout (Nt^-/-) mice were fed ad libitum or fasted for 48 hours. Small intestine tissue and crypts were examined by gene …

Association Between Obesity And Histological Tumor Budding In Patients With Nonmetastatic Colon Cancer, Tong Gan, Kurt B. Schaberg, Daheng He, Akila Mansour, Harit Kapoor, Chi Wang, B. Mark Evers, Therese J. Bocklage

Surgery Faculty Publications

Importance: Obesity is associated with increased risk of colorectal cancer (CRC) and a more aggressive disease course. Tumor budding (TB) is an important prognostic factor for CRC, but its association with obesity is unknown.

Objective: To evaluate the association of TB with obesity and other prognostic factors in colon cancer.

Design, Setting, and Participants: This cohort study involved a histological review of colon cancer specimens obtained during 7 years (January 2008 to December 2015) at the University of Kentucky Medical Center; data analysis was conducted from February 2020 to January 2021. Specimens came from 200 patients with stage I to …

Impact Of The Affordable Care Act On Colorectal Cancer Screening, Incidence, And Survival In Kentucky, Tong Gan, Heather F. Sinner, Samuel C. Walling, Quan Chen, Bin Huang, Thomas C. Tucker, Jitesh A. Patel, B. Mark Evers, Avinash S. Bhakta

Surgery Faculty Publications

Background

Kentucky ranks first in the US in cancer incidence and mortality. Compounded by high poverty levels and a high rate of medically uninsured, cancer rates are even worse in Appalachian Kentucky. Being one of the first states to adopt the Affordable Care Act (ACA) Medicaid expansion, insurance coverage markedly increased for Kentucky residents. The purpose of our study was to determine the impact of Medicaid expansion on colorectal cancer (CRC) screening, diagnosis, and survival in Kentucky.

Study Design

The Kentucky Cabinet for Health and Family Services and the Kentucky Cancer Registry were queried for individuals (≥20 years) undergoing CRC …

Tumorigenic Proteins Upregulated In The Mycn-Amplified Imr-32 Human Neuroblastoma Cells Promote Proliferation And Migration., Hayat Zaatiti, Jad Abdallah, Zeina Nasr, George Khazen, Anthony Sandler, Tamara J Abou-Antoun

Surgery Faculty Publications

Childhood neuroblastoma is one of the most common types of extra-cranial cancer affecting children with a clinical spectrum ranging from spontaneous regression to malignant and fatal progression. In order to improve the clinical outcomes of children with high-risk neuroblastoma, it is crucial to understand the tumorigenic mechanisms that govern its malignant behaviors. MYCN proto-oncogene, bHLH transcription factor (MYCN) amplification has been implicated in the malignant, treatment-evasive nature of aggressive, high-risk neuroblastoma. In this study, we used a SILAC approach to compare the proteomic signatures of MYCN-amplified IMR-32 and non-MYCN-amplified SK-N-SH human neuroblastoma cells. Tumorigenic proteins, including fatty-acid binding protein 5 …

The Role Of Tgf-Β/Smad4 Signaling In Cancer, M Zhao, Lopa Mishra, C Deng

Surgery Faculty Publications

Transforming growth factor β (TGF-β) signaling pathway plays important roles in many biological processes, including cell growth, differentiation, apoptosis, migration, as well as cancer initiation and progression. SMAD4, which serves as the central mediator of TGF-β signaling, is specifically inactivated in over half of pancreatic duct adenocarcinoma, and varying degrees in many other types of cancers. In the past two decades, multiple studies have revealed that SMAD4 loss on its own does not initiate tumor formation, but can promote tumor progression initiated by other genes, such as KRAS activation in pancreatic duct adenocarcinoma and APC inactivation in colorectal cancer. In …

Thyroid Cancer: Is It All In The Genes?, Electron Kebebew

Surgery Faculty Publications

No abstract provided.

Hic1 (Hypermethylated In Cancer 1) Sumoylation Is Dispensable For Dna Repair But Is Essential For The Apoptotic Dna Damage Response (Ddr) To Irreparable Dna Double-Strand Breaks (Dsbs)., Sonia Paget, Marion Dubuissez, Vanessa Dehennaut, Joe Nassour, Brennan T Harmon, Nathalie Spruyt, Ingrid Loison, Corinne Abbadie, Brian R Rood, Dominique Leprince

Surgery Faculty Publications

The tumor suppressor gene HIC1 (Hypermethylated In Cancer 1) encodes a transcriptional repressor mediating the p53-dependent apoptotic response to irreparable DNA double-strand breaks (DSBs) through direct transcriptional repression of SIRT1. HIC1 is also essential for DSB repair as silencing of endogenous HIC1 in BJ-hTERT fibroblasts significantly delays DNA repair in functional Comet assays. HIC1 SUMOylation favours its interaction with MTA1, a component of NuRD complexes. In contrast with irreparable DSBs induced by 16-hours of etoposide treatment, we show that repairable DSBs induced by 1 h etoposide treatment do not increase HIC1 SUMOylation or its interaction with MTA1. Furthermore, HIC1 SUMOylation …

Targeting Wnt/Β-Catenin Pathway In Hepatocellular Carcinoma Treatment, Valery Vilchez, Lilia M. Turcios, Francesc Marti, Roberto Gedaly

Surgery Faculty Publications

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Liver cancer is generally related to hepatitis B or C infection and cirrhosis. Usually, patients with HCC are asymptomatic and are diagnosed at late stages when surgical treatment is no longer suitable. Limited treatment options for patients with advanced HCC are a major concern. Therefore, there is an urge for finding novel therapies to treat HCC. Liver cancer is highly heterogeneous and involved deregulation of several signaling pathways. Wnt/β-catenin pathway is frequently upregulated in HCC and it is implicated in maintenance of tumor initiating cells, drug …

Mutational Profiles Reveal An Aberrant Tgf-Β-Cea Regulated Pathway In Colon Adenomas., Jian Chen, Gottumukkala S Raju, Wilma Jogunoori, Shoujun Gu, Lopa Mishra, + 27 More

Surgery Faculty Publications

Mutational processes and signatures that drive early tumorigenesis are centrally important for early cancer prevention. Yet, to date, biomarkers and risk factors for polyps (adenomas) that inordinately and rapidly develop into colon cancer remain poorly defined. Here, we describe surprisingly high mutational profiles through whole-genome sequence (WGS) analysis in 2 of 4 pairs of benign colorectal adenoma tissue samples. Unsupervised hierarchical clustered transcriptomic analysis of a further 7 pairs of adenomas reveals distinct mutational signatures regardless of adenoma size. Transitional single nucleotide substitutions of C:G>T:A predominate in the adenoma mutational spectrum. Strikingly, we observe mutations in the TGF-β pathway …

Vitamin D Deficiency Promotes Liver Tumor Growth In Transforming Growth Factor-Β/Smad3-Deficient Mice Through Wnt And Toll-Like Receptor 7 Pathway Modulation., Jian Chen, Lior H Katz, Nina M Muñoz, Shoujun Gu, Ji-Hyun Shin, Lopa Mishra, +13 Additional Authors

Surgery Faculty Publications

Disruption of the TGF-β pathway is associated with liver fibrosis and suppression of liver tumorigenesis, conditions associated with low Vitamin D (VD) levels. However, potential contributions of VD to liver tumor progression in the context of TGF-β signaling remain unexplored. Our analyses of VD deprivation (VDD) in in vivo models of liver tumor formation revealed striking three-fold increases in tumor burden in Smad3(+/-) mice, with a three-fold increase in TLR7 expression compared to controls. ChIP and transcriptional assays confirm Smad3 binding at two TLR7 promoter SBE sites. Molecular interactions between TGF-β pathway and VDD were validated clinically, where an absence …