Transcriptome and Proteome Analyses of TNFAIP8 Knockdown Cancer Cells Reveal New Insights into Molecular Determinants of Cell Survival and Tumor Progression

Abstract

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.

Androgen receptor inhibitor–induced “BRCAness” and PARP inhibition are synthetically lethal for castration-resistant prostate cancer

“…SGK1 and TNFAIP8 are two ENZ-downregulated and OLA upregulated anti-apoptotic genes identified in this study and knockdown of either gene was proved to have significant synergistic effect with PARP inhibition as regard to apoptotic cell death. These results suggest that downregulation of SGK1 and TNFAIP8 by ENZ prior to OLA treatment is, at least, one of the mechanisms underlying the superior effect of lead-in ENZ+OLA over concomitant ENZ+OLA; they are also consistent with growing evidence that links SGK1 and TNFAIP8 to cancer cell survival, metastasis and chemo- and radio-resistance (30–34). …”

“…Both SGK1 and TNFAIP8 reportedly participate in apoptosis evasion, cell survival, chemo resistance and tumor progression (Fig. 5E) (30–33) (34). Western blotting analysis validated select ENZ- and OLA-upregulated pro-apoptotic genes and ENZ-downregulated and OLA-upregulated SGK1 and TNFAIP8 (Fig.…”

Claudin7‐dependent exosome‐promoted reprogramming of nonmetastasizing tumor cells

“…Downstream signaling includes Rho‐GTPase, Ras‐GTPases and Akt. EphB3, engaged in cytoskeleton organization, is upregulated in colorectal cancer . Other activated RTK that could particularly contribute to the activation of cld7kd cells are INSR1 having docking sites for adaptor proteins with src‐2 domains .…”

“…EphB3, engaged in cytoskeleton organization, is upregulated in colorectal cancer. 48 Other activated RTK that could particularly contribute to the activation of cld7kd cells are INSR1 having docking sites for adaptor proteins with src-2 domains. 49 Insulin-like growth factor receptor (IGF1R) highly expressed in many cancer, is engaged in PI3K/Akt, MAPK and JNK cascade activation and IGF2R in TGFβ activation.…”

Differential Allele-Specific Expression Uncovers Breast Cancer Genes Dysregulated By Cis Noncoding Mutations

“…These appear upstream of KIF1B, TNFAIP8, PNN, FCF1, and PUDP, the first three of which have previously been associated with cancer. [57][58][59] Furthermore, four out of these five mutations are predicted by deepSEA to have a significant functional impact. Thus, the powerful filtering provided by differential ASE makes it possible to focus on only the subset of mutations that are potentially functional in whole genome sequencing.…”