Novel tumor necrosis factor-α induced protein eight (TNFAIP8/TIPE) family: Functions and downstream targets involved in cancer progression

doi:10.1016/j.canlet.2018.06.017

Cancer Letters

Volume 432, 28 September 2018, Pages 260-271

https://doi.org/10.1016/j.canlet.2018.06.017 Get rights and content

Highlights

•
TNF-α-induced protein 8 (TNFAIP8/TIPE) family members play an important role in a wide variety of physiological processes.
•
Their expression is also deregulated in diverse malignancies and mediates tumor initiation, promotion and progression.
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They may also have prognostic, diagnostic and therapeutic potential for cancer patients.

Abstract

The tumor necrosis factor (TNF)-α- induced protein 8 (TNFAIP8/TIPE) family is a death effector domain (DED)-containing protein family with four identified members: TNFAIP8 (TIPE), TNFAIP8L1 (TIPE1), TNFAIP8L2 (TIPE2), and TNFAIP8L3 (TIPE3). These proteins were found to play crucial roles in the regulation of immune homeostasis, inflammation, and cancer development. Intensive research in the past two decades revealed a strong correlation of TIPE proteins with the development of various cancers including cancers of the bladder, blood, bone, breast, cervix, colon, esophagus, endometrium, stomach, liver, lung, ovary, pancreas, prostate, and thyroid gland. Also, deregulation of these proteins was found to promote the essential hallmarks of cancer such as survival, tumor growth, proliferation, inhibition of apoptosis, angiogenesis, invasion, migration, and metastasis. Further, differential expression of these proteins in normal and cancer tissues and their association with tumor progression and prognosis signifies the potential diagnostic and prognostic values of TIPE proteins and their importance in cancer therapy. The current review summarizes the literature available thus far on the expression, function, and role of TIPE proteins in the development and maintenance of various cancers.

Introduction

Tumor necrosis factor (TNF)-α- induced protein 8 (TNFAIP8) is a recently identified protein family reported to have important roles in immunity, inflammation, and tumorigenesis [1]. The first member of this family was initially identified as a partial cDNA clone in late 1990s in head and neck squamous cell carcinoma (HNSCC) cells (PCI-06 B), derived from a metastatic radioresistant HNSCC patient and was initially called SCC-S2 [2]. However, the full length cDNA of SCC-S2 was isolated and characterized after 3 years of its identification and was found to encode a novel protein with high sequence homology to the death effector domain II (DED II) of cell death regulatory protein, Fas-associated death domain-like interleukin-1β-converting enzyme-inhibitory protein (FLIP). Interestingly, tumor necrosis factor-α (TNF-α) treatment was shown to induce steady state mRNA levels of SCC-S2 in a dose-dependent manner [3]. Consequently, three other proteins were identified to share high sequence and structural similarities with TNFAIP8 and thus were categorized into a protein family called TNFAIP8 [4]. Therefore, in brief, this protein family comprises of at least four TNF-α-inducible proteins, namely: TNFAIP8 (TIPE), TNFAIP8L1 (TIPE1), TNFAIP8L2 (TIPE2), and TNFAIP8L3 (TIPE3), and is considered as a new subfamily of death effector domain (DED) containing proteins as these proteins have a death effector domain (DED) in their structure [[3], [4], [5], [6], [7], [8]]. Moreover, these proteins were not found to have any significant homology with other proteins except the aforementioned minor sequence similarity within the DED [6]. However, within the family, all four proteins exhibit a high domain homology, including a highly conserved TIPE2 homology (TH) domain with seven α helices with a hydrophobic cavity through which these proteins interact with lipid messengers such as Phosphatidylinositol (3,4)-bisphosphate (PtdIns(3,4)P2), Phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2), Phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), Phosphatidylinositol 4-phosphate (PtdIns4P), Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3), and phosphatidic acid (PA) [6,9,10]. Despite this structural similarity, the biological functions of these proteins vary significantly. For instance, TIPE regulates cell growth, apoptosis, and helps in tumor metastasis; TIPE1 regulates autophagy; TIPE2 negatively regulates innate and cellular immunity; and TIPE3 binds and transports phosphoinositide second messengers. Additionally, all four proteins were implicated in the development and progression of a variety of cancers (Table 1) [[2], [3], [4], [5],8,9,11,12]. Therefore, the aim of the current review is to discuss the role of the TNFAIP8 protein family in the development and maintenance of various cancers based on current literature.

Section snippets

TNFAIP8 (TIPE)

Tumor necrosis factor (TNF)-α- induced protein 8, a 23 kDa cytosolic protein with a small DED at the amino terminus, which is homologous to DED II of FLIP and also known as SCC-S2, GG2-1, NDED, MDC-3.13, and TIPE, is the first discovered and most studied protein of the TNFAIP8 family [2,3,6,8]. As mentioned earlier, it was first identified in a head and neck squamous cell carcinoma cell line derived from a metastatic radioresistant HNSCC patient [2].

TNFAIP8L1 (TIPE1)

Tumor necrosis factor-α-induced protein 8-like 1 (TNFAIP8L1, TIPE1), another member of TNFAIP8 family, is a cytosolic protein first discovered by Sun et al. (2008) and not fully characterized. TIPE1 also shares a high sequence similarity and structural homology with other members of family [4,23]. Immunohistochemical and Western blot analyses of murine tissues and human cell lines with TIPE1-specific antibodies revealed that it is expressed in different C57BL/6 murine tissues, including

TNFAIP8L2 (TIPE2)

TIPE2, another well studied member of the TNFAIP8 family is mostly a cytosolic protein; however, its expression is also detected in the nucleus [4,54,55]. A BLAST search of TIPE2 revealed that it possesses 94% sequence identity with murine TIPE2 and 53% sequence identity with human TIPE. Like TIPE, it also contains an N-terminus DED domain with 6 conserved α-helices [4,5,56]. It was first identified in experimental autoimmune encephalomyelitis and found to be highly expressed in inflamed spinal

TNFAIP8L3 (TIPE3)

Only very few reports are available on TIPE3, a new member of the TNFAIP8 family, with high structural and sequence homology with the other family members, and little is known about its biological function [6,23]. Recently, the crystal structure of TIPE3 was determined and the actual role of TIPE3 was identified. The structural information revealed that, similar to its homologous proteins, TIPE3 also contains a TH fold with a large hydrophobic cavity, suggesting a possible lipid binding ability

Conclusion

The last two decades of research have exemplified the expression pattern and importance of the TNFAIP8 family in biological systems. Apart from regulating several important biological functions including immunity, inflammation, cell survival, proliferation, and cell death, members of this protein family were also found to play key roles in migration, invasion, and malignant transformation in different neoplasms. Interestingly, considering the sequence and structural similarities, the effect of

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgement

This work was supported by BT/529/NE/TBP/2013 awarded to Ajaikumar B Kunnumakkara by Department of Biotechnology (DBT), Government of India. The author Kishore Banik acknowledges the UGC New Delhi, for providing him the fellowship.

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Mini-reviewNovel tumor necrosis factor-α induced protein eight (TNFAIP8/TIPE) family: Functions and downstream targets involved in cancer progression

Highlights

Abstract

Introduction

Section snippets

TNFAIP8 (TIPE)

TNFAIP8L1 (TIPE1)

TNFAIP8L2 (TIPE2)

TNFAIP8L3 (TIPE3)

Conclusion

Conflicts of interest

Acknowledgement

Oral Oncology

J. Biol. Chem.

Cell

Cell

Mol. Immunol.

J. Biol. Chem.

Canc. Cell

Mol. Ther.: The Journal of the American Society of Gene Therapy

Blood

J. Biol. Chem.

Mol. Oncol.

Hum. Pathol.

Hum. Pathol.

Mol. Immunol.

Cell

Cell

Mol. Immunol.

Mol. Immunol.

J. Neuroimmunol.

J. Biol. Chem.

Biochim. Biophys. Acta

Mol. Immunol.

Mol. Immunol.

J. Biol. Chem.

Mol. Cell

Oncol.Lett.

Biochem. Biophys. Res. Commun.

Mol. Immunol.

Canc. Biomarkers: Section a of Disease Markers

Canc. Cell

Regulation of inflammation and tumorigenesis by the TIPE family of phospholipid transfer proteins

Cell. Mol. Immunol.

Expression of SCC-S2, an antiapoptotic molecule, correlates with enhanced proliferation and tumorigenicity of MDA-MB 435 cells

Oncogene

Molecular insights into the binding of phosphoinositides to the TH domain region of TIPE proteins

J. Mol. Model.

Tnfaip8 l1/Oxi-beta binds to FBXW5, increasing autophagy through activation of TSC2 in a Parkinson's disease model

J. Neurochem.

The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression

Cell Death and Differentiation

MicroRNA-9 inhibits the gastric cancer cell proliferation by targeting TNFAIP8

Cell Proliferation

Tumor-suppressive miR-99a inhibits cell proliferation via targeting of TNFAIP8 in osteosarcoma cells

Am. J. Tourism Res.

MicroRNA-138 directly targets TNFAIP8 and acts as a tumor suppressor in osteosarcoma

J. Exp. Therapeut. Med.

Transcriptome and proteome analyses of TNFAIP8 knockdown cancer cells reveal new insights into molecular determinants of cell survival and tumor progression

Meth. Mol. Biol.

TNFAIP8 interacts with LATS1 and promotes aggressiveness through regulation of Hippo pathway in hepatocellular carcinoma

OncoTargets Ther.

SCC-S2 is overexpressed in colon cancers and regulates cell proliferation

Thumour.bio: The Journal of the International Society for Oncodevelopmental Biology and Medicine

The tumor necrosis factor-alpha-induced protein 8 family in immune homeostasis and inflammatory cancer diseases

J. Biol. Regul. Homeost. Agents

TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation

J. Cell. Physiol.

Tnfaip8 is an essential gene for the regulation of glucocorticoid-mediated apoptosis of thymocytes

Cell Death and Differentiation

Two genes on A/J chromosome 18 are associated with susceptibility to Staphylococcus aureus infection by combined microarray and QTL analyses

PLoS Pathogens

Exacerbated experimental colitis in TNFAIP8-deficient mice

J. Immunol.

Effect of tumor necrosis factor-induced protein 8 on T-cell-mediated immunity in mice after thermal injury

J. Biol. Regul. Homeost. Agents

Mini-review
Novel tumor necrosis factor-α induced protein eight (TNFAIP8/TIPE) family: Functions and downstream targets involved in cancer progression