Transcriptome and Proteome Analyses of TNFAIP8 Knockdown Cancer Cells Reveal New Insights into Molecular Determinants of Cell Survival and Tumor Progression.
Tumor necrosis factor-α-inducible protein 8 (TNFAIP8) is the first discovered oncogenic and an anti-apoptotic member of a conserved TNFAIP8 or TIPE family of proteins. TNFAIP8 mRNA is induced by NF-kB, and overexpression of TNFAIP8 has been correlated with poor prognosis in many cancers. Downregulation of TNFAIP8 expression has been associated with decreased pulmonary colonization of human tumor cells, and enhanced sensitivities of tumor xenografts to radiation and docetaxel. Here we have investigated the effects of depletion of TNFAIP8 on the mRNA, microRNA and protein expression profiles in prostate and breast cancers and melanoma. Depending on the tumor cell type, knockdown of TNFAIP8 was found to be associated with increased mRNA expression of several antiproliferative and apoptotic genes (e.g., IL-24, FAT3, LPHN2, EPHA3) and fatty acid oxidation gene ACADL, and decreased mRNA levels of oncogenes (e.g., NFAT5, MALAT1, MET, FOXA1, KRAS, S100P, OSTF1) and glutamate transporter gene SLC1A1. TNFAIP8 knockdown cells also exhibited decreased expression of multiple onco-proteins (e.g., PIK3CA, SRC, EGFR, IL5, ABL1, GAP43), and increased expression of the orphan nuclear receptor NR4A1 and alpha 1 adaptin subunit of the adaptor-related protein complex 2 AP2 critical to clathrin-mediated endocytosis. TNFAIP8-centric molecules were found to be predominately implicated in the hypoxia-inducible factor-1α (HIF-1α) signaling pathway, and cancer and development signaling networks. Thus TNFAIP8 seems to regulate the cell survival and cancer progression processes in a multifaceted manner. Future validation of the molecules identified in this study is likely to lead to new subset of molecules and functional determinants of cancer cell survival and progression.
Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Rd, NW, Washington, DC, 20057, USA.
Timothy F
TF
Day
Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Rd, NW, Washington, DC, 20057, USA.
Rajshree R
RR
Mewani
Department of Anatomy, Physiology and Genetics, Institute for Molecular Medicine, Center for Medical Proteomics, Uniformed Services University School of Medicine, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
Joshua
J
Starr
Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Rd, NW, Washington, DC, 20057, USA.
Xin
X
Li
Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Rd, NW, Washington, DC, 20057, USA.
Debyani
D
Chakravarty
Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Rd, NW, Washington, DC, 20057, USA.
Habtom
H
Ressom
Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Rd, NW, Washington, DC, 20057, USA.
Xiaojun
X
Zou
Department of Anatomy, Physiology and Genetics, Institute for Molecular Medicine, Center for Medical Proteomics, Uniformed Services University School of Medicine, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
Ofer
O
Eidelman
Department of Anatomy, Physiology and Genetics, Institute for Molecular Medicine, Center for Medical Proteomics, Uniformed Services University School of Medicine, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
Harvey B
HB
Pollard
Department of Anatomy, Physiology and Genetics, Institute for Molecular Medicine, Center for Medical Proteomics, Uniformed Services University School of Medicine, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
Meera
M
Srivastava
Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Rd, NW, Washington, DC, 20057, USA. kasidu@georgetown.edu.
Usha N
UN
Kasid
D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival; D018450:Disease Progression; D050580:Excitatory Amino Acid Transporter 3 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008545:Melanoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D040901:Proteomics / Q000379:methods*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
D051017:Apoptosis Regulatory Proteins; D050580:Excitatory Amino Acid Transporter 3; D016328:NF-kappa B; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; C493400:SLC1A1 protein, human; C404190:TNFAIP8 protein, human
Antibody arrays; Cancer systems biology; Cell survival and proliferation; Invasion and metastasis; RNA and microRNA arrays; TNFAIP8; shRNA and siRNA