TRIB2 functions as novel oncogene in colorectal cancer by blocking cellular senescence through AP4/p21 signaling

Abstract

BackgroundCellular senescence is a state of irreversible cell growth arrest and senescence cells permanently lose proliferation potential. Induction of cellular senescence might be a novel therapy for cancer cells. TRIB2 has been reported to participate in regulating proliferation and drug resistance of various cancer cells. However, the role of TRIB2 in cellular senescence of colorectal cancer (CRC) and its molecular mechanism remains unclear.MethodsThe expression of TRIB2 in colorectal cancer tissues and adjacent tissues was detected by immunohistochemistry and RT-PCR. The growth, cell cycle distribution and cellular senescence of colorectal cancer cells were evaluated by Cell Counting Kit-8 (CCK8) assay, flow cytometry detection and senescence-associated β-galactosidase staining, respectively. Western blot, RT-PCR and luciferase assay were performed to determine how TRIB2 regulates p21. Immunoprecipitation (IP) and chromatin-immunoprecipitation (ChIP) were used to investigate the molecular mechanisms.ResultsWe found that TRIB2 expression was elevated in CRC tissues compared to normal adjacent tissues and high TRIB2 expression indicated poor prognosis of CRC patients. Functionally, depletion of TRIB2 inhibited cancer cells proliferation, induced cell cycle arrest and promoted cellular senescence, whereas overexpression of TRIB2 accelerated cell growth, cell cycle progression and blocked cellular senescence. Further studies showed that TRIB2 physically interacted with AP4 and inhibited p21 expression through enhancing transcription activities of AP4. The rescue experiments indicated that silencing of AP4 abrogated the inhibition of cellular senescence induced by TRIB2 overexpression.ConclusionThese data demonstrate that TRIB2 suppresses cellular senescence through interaction with AP4 to down-regulate p21 expression. Therefore, TRIB2 could be a potential target for CRC treatment.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0922-x) contains supplementary material, which is available to authorized users.

LncRNA XIST promotes the progression of laryngeal squamous cell carcinoma via sponging miR-125b-5p to modulate TRIB2

“…Tribbles homolog 2 (TRIB2) belongs to Tribbles pseudokinases, playing a pivotal role in etiology of multifarious cancers [26,27]. Investigators found TRIB2 expression was elevated in colorectal cancer (CRC) and TRIB2 overexpression promoted cell proliferation and deferred cellular senescence of CRC partially relying on direct regulation of p21 expression and transcription factor AP4 expression [28]. In another study, promoter activity of TRIB2 might be declined in miR-206/miR-140-elevated lung adenocarcinoma cell, weakening cell invasive ability and proliferation [29].…”

Combined elevation of TRIB2 and MAP3K1 indicates poor prognosis and chemoresistance to temozolomide in glioblastoma

“…Abnormally elevated TRIB2 was previously identified as the clinically relevant factor in various subtypes of human cancers . As described previously, TRIB2 promotes tumorigenesis and induces therapeutic resistance by activating Wnt‐mediated downstream activation of Hippo signaling and the YAP pathway through transcriptional control of gene expression and TRIB2‐mediated posttranslational regulation of protein stability in liver cancer cells .…”

“…Abnormally elevated TRIB2 was previously identified as the clinically relevant factor in various subtypes of human cancers. [5][6][7][8] As MAP3K1 is a 196-kDa serine/threonine kinase that is activated by various stimuli and cell stresses, including growth factors, cytokines, and microtubule disruption. 35 Our present study showed elevated MAP3K1 expression in glioma, which is conversely associated with a poor prognosis and therapeutic resistance in glioma.…”

“…5 Recent studies have indicated that TRIB2 functions as a crucial oncogene that regulates a wide range of cellular processes, including tumorigenesis, proliferation, invasion, and therapeutic resistance, in various subtypes of cancer, such as small cell lung cancer, liver cancers, colorectal cancer, and acute myeloid leukemia. [5][6][7][8] Foulkes et al 9 demonstrated that TRIB2 expression is significantly increased in acute myeloid leukemia and promotes tumor proliferation by inactivating CCAATenhancer-binding protein α (C/EBPα). Moreover, Wnt/TCF signaling-dependent activation of TRIB2 stimulates the proliferation of liver cancer cells through a stabilization effect on yes-associated protein (YAP).…”

miR-509-5p Inhibits the Proliferation and Invasion of Osteosarcoma by Targeting TRIB2

“…Although miR-509-5p should have many targets, for example, MDM2, SOD2, FOXP1, etc., we identified TRIB2 as a direct target of miR-509-5p while it is a putative oncogene that is also highly expressed in OS tissues. Furthermore, the result of subsequent luciferase reporter gene suggested that TRIB2 inhibited the bioactivity of a well-recognized tumor suppressor gene, p21, through blocking its transcriptional activity [17]. In conclusion, miR-509-5p acts as an antitumor gene in OS through inhibiting the expression of TRIB2, an oncogene that decreased the expression of p21 and attenuated the antitumor function, thus increasing cancer risk and accelerating the OS progression.…”