The E3 ubiquitin ligase TRIM7 suppressed hepatocellular carcinoma progression by directly targeting Src protein

Zhu, Lihui; Qin, Chengyong; Li, Tao; Ma, Xiaomin; Qiu, Yumin; Lin, Yueke; Ma, Dapeng; Qin, Zhenzhi; Sun, Caiyu; Shen, Xiaoxu; Zhao, Yunxue; Han, Lihui

doi:10.1038/s41418-019-0464-9

Cited by 50 publications

(52 citation statements)

References 35 publications

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“…The upregulation of BNIP3 enhanced the activation of autophagy and anoikis resistance of HCC cells by suppressing mTOR/S6K1 signaling pathway 34 . Tripartite motif‐containing 7 suppressed HCC progression through modulation of the Src‐mTORC1‐S6K1 axis 35 . In line with the above findings, our data displayed that BUB1B could stimulate the mTORC1 signaling pathway to promote HCC progression, which was a brand‐new mechanism of BUB1B in the progression of tumor.…”

Section: Discussionsupporting

confidence: 81%

BUB1B promotes hepatocellular carcinoma progression via activation of the mTORC1 signaling pathway

et al. 2020

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Background and Aims Accumulating studies identified that BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) is integrally involved in the initiation and development of tumors. Nevertheless, the precise biological role and underlying mechanisms of BUB1B in hepatocellular carcinoma (HCC) remain indistinct. Method To figure out the role of BUB1B in HCC, we first assessed its expression using The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA) databases. We then verified BUB1B expression in HCC tissues, nontumor tissues, and HCC cell lines through western blotting, quantitative reverse transcription‐polymerase chain reaction, and immunohistochemistry. To explore the specific function of BUB1B in HCC in vivo and in vitro, we performed the flow cytometry, Cell Counting Kit‐8, 5‐ethynyl‐2′‐deoxyuridine incorporation, colony formation, Transwell, wound‐healing, subcutaneous tumor growth, and metastasis assays. Additionally, we identified the BUB1B‐regulated pathways involved in HCC by using gene set enrichment analysis. Results Our data displayed that higher BUB1B expression was detected in HCC tissues and HCC cell lines. The overexpression of BUB1B was positively correlated with adverse clinicopathological characteristics. Survival analyses showed that lower recurrence‐free and overall survival rates were correlated with the overexpression of BUB1B in patients with HCC. Moreover, the malignancy of HCC was facilitated by BUB1B both in vivo and in vitro. Lastly, the results were confirmed by western blots, which showed that BUB1B upregulated mTORC1 signaling pathway in HCC. Meanwhile, the oncogenic effect of BUB1B will be impaired when the mTORC1 signaling pathway was inhibited by rapamycin. Conclusion We highlighted that BUB1B played an oncogenic role in HCC and was identified as a possible clinical prognostic factor and a potential novel therapeutic target for HCC.

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Section: Discussionsupporting

confidence: 81%

BUB1B promotes hepatocellular carcinoma progression via activation of the mTORC1 signaling pathway

et al. 2020

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“…TRIM7 is also overexpressed in human lung adenocarcinomas, and its depletion suppresses cell growth of primary murine lung adenocarcinoma as well as significantly decreases tumour growth in xenograft mice after doxycycline treatment [11] . Meanwhile, TRIM7 suppresses hepatocellular carcinoma progression by directly targeting Src protein [12] and regulates hepatocellular carcinoma cell proliferation via the DUSP6/p38 pathway [13] . TRIM7 has also been found to be positively regulated by CD26, a protein closely linked to cell cycle progress, apoptosis, and chemotherapy resistance in malignant pleural mesothelioma [14] .…”

Section: Introductionmentioning

confidence: 99%

N6-Methyladenosine modification of the TRIM7 positively regulates tumorigenesis and chemoresistance in osteosarcoma through ubiquitination of BRMS1

Zhou

Zhang

Zhu³

et al. 2020

eBioMedicine

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Background Metastasis is the leading cause of death in patients with osteosarcoma. Some of these patients fail to respond to chemotherapy and die of metastasis within a short period. Therefore, it is important to identify novel biomarkers to improve the diagnosis and treatment of osteosarcoma. TRIM7 is a member of the tripartite motif (TRIM) family protein that is involved in various pathological conditions including cancer; however, its role in osteosarcoma remains elusive. Methods Cell proliferation, invasion and migration were measured by CCK-8 and Transwell. Immunoprecipitation and mass spectrometry analysis were used to identify candidate proteins associated with TRIM7. Immunoprecipitation, immunofluorescence, pull down and ubiquitination assay were performed to examine the regulation between TRIM7 and its candidate protein. m6A modification of TRIM7 was measured by RNA immunoprecipitation. Findings TRIM7 expression was upregulated in osteosarcoma tissues and was an independent risk factor in predicting poor prognosis. TRIM7 regulates osteosarcoma cell migration and invasion through ubiquitination of breast cancer metastasis suppressor 1 (BRMS1). Moreover, chemoresistance was readily observed in osteosarcoma cells and in patient-derived xenograft (PDX) mice with higher TRIM7 levels. Loss of TRIM7 m6A modification was observed in osteosarcoma tissues. METTL3 and YTHDF2 were the main factors involved in the aberrant m6A modification of TRIM7. Interpretation Overall, our findings show that TRIM7 plays a key role in regulating metastasis and chemoresistance in osteosarcoma through ubiquitination of BRMS1. Funding This work was financially supported by grants of NSFC (81001192, 81672658 and 81972521) and National Key Research Project of Science and Technology Ministry (2016YFC0106204).

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“…For example, KRAS is usually found mutated in CCA patients [ 51 , 52 ]. The proto-oncogene tyrosine kinase Src is usually aberrantly expressed in HCC with an effect on cell proliferation, differentiation [ 53 – 56 ]. Meanwhile, mucin 5AC (MUC5AC) as a secreted Mucins was upregulated in ICC and CHC patient and inflammation [ 57 ].…”

Section: Resultsmentioning

confidence: 99%

ORN: Inferring patient-specific dysregulation status of pathway modules in cancer with OR-gate Network

et al. 2021

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Pathway level understanding of cancer plays a key role in precision oncology. However, the current amount of high-throughput data cannot support the elucidation of full pathway topology. In this study, instead of directly learning the pathway network, we adapted the probabilistic OR gate to model the modular structure of pathways and regulon. The resulting model, OR-gate Network (ORN), can simultaneously infer pathway modules of somatic alterations, patient-specific pathway dysregulation status, and downstream regulon. In a trained ORN, the differentially expressed genes (DEGs) in each tumour can be explained by somatic mutations perturbing a pathway module. Furthermore, the ORN handles one of the most important properties of pathway perturbation in tumours, the mutual exclusivity. We have applied the ORN to lower-grade glioma (LGG) samples and liver hepatocellular carcinoma (LIHC) samples in TCGA and breast cancer samples from METABRIC. Both datasets have shown abnormal pathway activities related to immune response and cell cycles. In LGG samples, ORN identified pathway modules closely related to glioma development and revealed two pathways closely related to patient survival. We had similar results with LIHC samples. Additional results from the METABRIC datasets showed that ORN could characterize critical mechanisms of cancer and connect them to less studied somatic mutations (e.g., BAP1, MIR604, MICAL3, and telomere activities), which may generate novel hypothesis for targeted therapy.

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The E3 ubiquitin ligase TRIM7 suppressed hepatocellular carcinoma progression by directly targeting Src protein

Cited by 50 publications

References 35 publications

BUB1B promotes hepatocellular carcinoma progression via activation of the mTORC1 signaling pathway

BUB1B promotes hepatocellular carcinoma progression via activation of the mTORC1 signaling pathway

N6-Methyladenosine modification of the TRIM7 positively regulates tumorigenesis and chemoresistance in osteosarcoma through ubiquitination of BRMS1

ORN: Inferring patient-specific dysregulation status of pathway modules in cancer with OR-gate Network

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