Thirty‐kilodalton Tat‐interacting protein suppresses tumor metastasis by inhibition of osteopontin transcription in human hepatocellular carcinoma†

Zhao, Jian; Lü, Bin; Xu, Hao; Tong, Xin; Wu, Guobin; Zhang, Xia; Liang, Anmin; Wang, Cong; Dai, Jing; Wang, Hao; Wu, Mengchao; Guo, Yajun

doi:10.1002/hep.22280

Cited by 47 publications

(46 citation statements)

References 36 publications

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“…9 Our recent studies showed that TIP30 inhibited tumor metastasis through suppressing the expression of OPN in human hepatocellular carcinoma. 16 The role of TIP30 in the development and progression of lung cancer has not been fully characterized. In the present study, TIP30 expression was examined by immunohistochemistry in 206 lung carcinoma tissues, including 197 non-small cell lung cancers (NSCLC) and 9 SCLCs, and adjacent non-tumor tissues, as well as 70 matched lymph node metastases using a high-density tissue microarray.…”

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Decreased TIP30 Expression Promotes Tumor Metastasis in Lung Cancer

Tong

Luo

et al. 2009

The American Journal of Pathology

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The HIV Tat-interacting protein (TIP30), also called CC3 or HTIP2, is encoded by Tip30, a putative tumorsuppressor gene located on human chromosome 11p15.1. In this study, we investigated the role of TIP30 in the progression and metastasis of lung cancer. TIP30 expression was analyzed in 206 paired lung cancers and adjacent non-tumor tissues, as well as in 70 matched lymph node metastases using a high-density tissue microarray. Results were compared with the clinicopathologic features of the patients from whom the tissues were taken. Low TIP30 expression levels were found in all 9 cases of small cell lung cancer and in 36.5% (72/197) of non-small cell lung cancer, which were correlated with lymph node metastasis in non-small cell lung cancer and with poor differentiation and advanced stage of tumor cells in squamous cell carcinoma. The immunostaining scores were significantly lower in the metastatic lesions than in the primary lesions. Down-regulation of TIP30 by a short hairpin RNA enhanced cell survival, migration, and invasion through Matrigel in vitro, and promoted lung metastasis and vascularization in nude mice. Further studies revealed that the downregulation of TIP30 enhanced the expression of osteopontin, as well as matrix metalloproteinase-2 and vascular endothelial growth factor. Our results suggest that the down-regulation of TIP30 promotes metastatic progression of lung cancer, hence it could serve as a potential target for the development of lung cancer therapies.

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“…15 Recently TIP30 was found to interact with Ets-1 and inhibit osteopontin (OPN) transcription. 16 Recent studies have linked TIP30 to metastatic progression of several different cancer types. Introduction of TIP30 into v-SCLC cells suppressed metastasis in SCIDhu-L mice.…”

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Decreased TIP30 Expression Promotes Tumor Metastasis in Lung Cancer

Tong

Luo

et al. 2009

The American Journal of Pathology

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“…Deletion of Rab5a in cells inhibits the transport of EGFR from early endosomes to lysosomes and consequently causes sustained EGFR signaling and delayed EGFR degradation (19). Despite its importance to endocytic transport, how Rab5a mediates downregulation of receptor signaling remains unclear.TIP30, also known as HTATIP2 or CC3 (20, 21), is a tumor suppressor that has been demonstrated to act as a transcription cofactor to repress transcription in the nucleus (22,23) and to localize at the nuclear envelope to block nuclear importing (24). However, TIP30 also localizes in the cytoplasm, where its function is not known (25-28).…”

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confidence: 99%

“…TIP30, also known as HTATIP2 or CC3 (20, 21), is a tumor suppressor that has been demonstrated to act as a transcription cofactor to repress transcription in the nucleus (22,23) and to localize at the nuclear envelope to block nuclear importing (24). However, TIP30 also localizes in the cytoplasm, where its function is not known (25-28).…”

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A Novel TIP30 Protein Complex Regulates EGF Receptor Signaling and Endocytic Degradation

Zhang

et al. 2011

Journal of Biological Chemistry

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Activated epidermal growth factor receptor (EGFR) continues to signal in the early endosome, but how this signaling process is regulated is less well understood. Here we describe a protein complex consisting of TIP30, endophilin B1, and acyl-CoA synthetase long chain family member 4 (ACSL4) that interacts with Rab5a and regulates EGFR endocytosis and signaling. Receptor-mediated endocytosis is a mechanism utilized by eukaryotic cells to rapidly take up specific nutrients and reduce receptor signaling at the plasma membrane. Internalized ligand-receptor complexes are enclosed in early endosomes, also called sorting endosomes, where they are either recycled or delivered to lysosomes for destruction (1, 2). Signaling receptors continue to activate certain downstream pathways from early endosomes (3-6) until ligand-receptor complexes dissociate due to lower luminal pH created by vacuolar V-ATPases, 2 the major proton pump responsible for endosomal and lysosomal acidification (2, 7-9). Inactivation of V-ATPases blocks the transition from early to late endosomes (10). Therefore, the proper endosomal targeting and activity of V-ATPases contribute to the tight regulation of both endocytic trafficking and receptor endosomal signaling.Acidic luminal pH in early endosomes is the driving force for receptors to release their ligands, such as insulin and low density lipoprotein (LDL) (1, 2). On the basis of individually tracking EGF and EGFR, it has long been considered that EGFR travels together with EGF until they reach lysosomes (11, 12). However, it is unclear whether they remain bound to each other on the way to lysosomes. Recent studies have suggested that EGFR is inactivated before being degraded and that EGF dissociates from EGFR prior to lysosomal transfer (6, 13-15).Rab5a is a small GTPase that regulates early endosome fusion in vitro (16), motility of early endosomes on microtubules (17), and the traffic between endosomes and lysosomes (18). Deletion of Rab5a in cells inhibits the transport of EGFR from early endosomes to lysosomes and consequently causes sustained EGFR signaling and delayed EGFR degradation (19). Despite its importance to endocytic transport, how Rab5a mediates downregulation of receptor signaling remains unclear.TIP30, also known as HTATIP2 or CC3 (20, 21), is a tumor suppressor that has been demonstrated to act as a transcription cofactor to repress transcription in the nucleus (22,23) and to localize at the nuclear envelope to block nuclear importing (24). However, TIP30 also localizes in the cytoplasm, where its function is not known (25-28).Here we report that a newly identified protein complex containing TIP30, ACSL4, and Endo B1 drives EGF-EGFR complex endocytic trafficking by facilitating the localization of Rab5a and V-ATPases to early endosomes. Rab5a and V-ATPase reside in vesicles devoid of the early endosomal marker EEA1 and the recycling endosomal marker transferrin receptor (TfR), suggesting that these vesicles are post-trans-Golgi network vesicles responsible for the transport of i...

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“…It is known to be upregulated by heat shock, stress, aging, certain viruses, and the cytokine TGF-β. The tumor-suppressive activity of TIP30 has been linked to the induction of apoptosis, possibly by blocking of nuclear pores (11), and the suppression of osteopontin (14), a proinflammatory cytokine that has been implicated in the generation of Th17 cells, important for the generation of cell-mediated immunity. Osteopontin has been shown to be upregulated in chronic active MS lesions and has been linked to the exacerbation of the animal model for MS known as EAE (15).…”

Section: Potential Role Of Tip30 In Ms Pathogenesismentioning

confidence: 99%