TRIM21 is a novel regulator of Par-4 in colon and pancreatic cancer cells

Nguyen, Jimmy; Irby, Rosalyn

doi:10.1080/15384047.2016.1252880

Cited by 49 publications

(39 citation statements)

References 40 publications

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“…S100A10, a small dimeric helix-loop-helix protein residing in a tight complex with Annexin A2, appeared to regulate the intracellular trafficking of a variety of membrane-resident proteins, such as cathepsin B (38). TRIM21 is an E3 ubiquitin ligase associated with autoimmune diseases (39), and the dysregulation of TRIM21 facilitates human cancer development (40,41). This study detected a significant decrease of TRIM21 and Annexin A2 levels in PGCCs with their daughter cells after S100A4 knockdown as well as a reduced nuclear translocation of S100A10 in daughter cells, while 14-3-3 ζ/δ and Ezrin did not vary.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms by Which S100A4 Regulates the Migration and Invasion of PGCCs With Their Daughter Cells in Human Colorectal Cancer

Fei

et al. 2020

Front. Oncol.

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Recently, an increasing number of evidences have shown that polyploid giant cancer cells (PGCCs) could generate daughter cells with a strong migration and invasion ability, which have been implicated in cancer recurrence and metastasis. However, the underlying molecular mechanisms of PGCCs with their daughter cells remain largely unclear. In vitro and in vivo experiments combined with 222 cases of human colorectal cancer (CRC) samples were used to identify the molecular mechanisms of S100A4-related proteins regulating the invasion and metastasis of PGCCs with their daughter cells. PGCCs with their daughter cells had high migration, invasion, and proliferation abilities compared to control cells; these were significantly inhibited after S100A4 knockdown. The high expression of cathepsin B, cyclin B1, TRIM21, and Annexin A2 were significantly downregulated after S100A4 knockdown, while the overexpression of S100A4, cathepsin B, cyclin B1, and S100A10 were significantly downregulated after TRIM21 knockdown in PGCCs with their daughter cells. The tumorigenic and metastatic ability of PGCCs with their daughter cells in vivo was significantly stronger compared to the untreated cells, which was significantly decreased after S100A4 knockdown. Moreover, the expression of S100A4-related proteins was positively correlated with the malignancy degree of human CRC, and maintained a high level in lymph node metastasis. S100A4 and TRIM21 may regulate each other to affect the expression and subcellular localization of cyclin B1, and participate in regulating the structure and function of Annexin A2/S100A10 complex, affecting downstream cathepsin B, resulting in the invasion and metastasis of PGCCs with their daughter cells. Besides, 14-3-3 ζ/δ and Ezrin may be involved in the motility and invasion of PGCCs with their daughter cells via cytoskeletal constructions with S100A4.

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Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms by Which S100A4 Regulates the Migration and Invasion of PGCCs With Their Daughter Cells in Human Colorectal Cancer

Fei

et al. 2020

Front. Oncol.

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“… 22 The literature reports that decreased expression of TRIM21 predicts shorter survival times in patients with hepatocellular carcinoma and diffuse large B-cell lymphoma 8 , 9 but better prognosis in patients with pancreatic cancer. 11 TRIM21 has also been identified as a diagnostic biomarker for breast cancer. 23 In our study, TRIM21 was noticeably downregulated in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

“… 10 TRIM21 confers drug resistance to cisplatin to colon cancer cells via the suppression of Par-4. 11 In breast cancer, TRIM21 was found to be capable of downregulating the expression of Sal-like 4 (SALL4) and Lifeguard. 12 , 13 However, the clinical significance of TRIM21 and its role in cell proliferation in breast cancer remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Decreased expression of TRIM21 indicates unfavorable outcome and promotes cell growth in breast cancer

Zhou

Zhang

Zhong

et al. 2018

CMAR

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BackgroundTripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin ligase, has been implicated in autoimmune diseases. Dysregulation of TRIM21 contributes to the progression of human malignancies, but its role and clinical significance in breast cancer remain unclear.MethodsThe expression of TRIM21 was examined by quantitative real-time PCR, Western blot, and immunohistochemistry. The role of TRIM21 in the progression of breast cancer was determined using in vitro and in vivo models. The upstream regulation of TRIM21 was investigated by luciferase reporter assay.ResultsHere, we showed that TRIM21 expression in breast cancer tissues was decreased at both the mRNA and protein levels in comparison to that in nontumorous tissues. TRIM21 expression was closely associated with tumor size, estrogen receptor, human epidermal growth factor receptor 2, and clinical stage. Low TRIM21 expression was correlated with poor overall and disease-free survival in two independent cohorts containing 1,219 patients with breast cancer. A multivariate Cox regression model suggested TRIM21 as an independent factor for overall survival. In vitro data revealed that TRIM21 expression was suppressed by miR-494-3p directly targeting the 3′ untranslated region of TRIM21. Overexpression of TRIM21 impeded cell proliferation and tumor growth in breast cancer, whereas TRIM21 depletion enhanced these capacities.ConclusionCollectively, our findings indicate that TRIM21 serves as a potential prognostic biomarker and functions as a tumor suppressor in breast cancer.

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“…TRIM21 was originally identified as an autoantigen in autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus (SLE), and Sjogren's syndrome (39). Recent studies have suggested that TRIM21 may play an essential role in the tumor suppressor or drug-induced apoptosis of cancer cells (41,42). However, contradictory results, that TRIM21 may target IRF3 after RNA viral infection, have been reported (43,44).…”

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confidence: 99%

TRIM21 Promotes Innate Immune Response to RNA Viral Infection through Lys27-Linked Polyubiquitination of MAVS

Xue

Guo

et al. 2018

J Virol

118

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Human innate immunity responds to viral infection by activating the production of interferons (IFNs) and proinflammatory cytokines. The mitochondrial adaptor molecule MAVS plays a critical role in innate immune response to viral infection. In this study, we show that TRIM21 (tripartite motif-containing protein 21) interacts with MAVS to positively regulate innate immunity. Under viral infection, TRIM21 is upregulated through the IFN/JAK/STAT signaling pathway. Knockdown of TRIM21 dramatically impairs innate immune response to viral infection. Moreover, TRIM21 interacts with MAVS and catalyzes its K27-linked polyubiquitination, thereby promoting the recruitment of TBK1 to MAVS. Specifically, the PRY-SPRY domain of TRIM21 is the key domain for its interaction with MAVS, while the RING domain of TRIM21 facilitates the polyubiquitination chains of MAVS. In addition, the MAVS-mediated innate immune response is enhanced by both the PRY-SPRY and RING domains of TRIM21. Mutation analyses of all the lysine residues of MAVS further revealed that Lys325 of MAVS is catalyzed by TRIM21 for the K27-linked polyubiquitination. Overall, this study reveals a novel mechanism by which TRIM21 promotes the K27-linked polyubiquitination of MAVS to positively regulate innate immune response, thereby inhibiting viral infection. IMPORTANCE Activation of innate immunity is essential for host cells to restrict the spread of invading viruses and other pathogens. MAVS plays a critical role in innate immune response to RNA viral infection. In this study, we demonstrated that TRIM21 targets MAVS to positively regulate innate immunity. Notably, TRIM21 targets and catalyzes K27-linked polyubiquitination of MAVS and then promotes the recruitment of TBK1 to MAVS, leading to upregulation of innate immunity. Our study outlines a novel mechanism by which the IFN signaling pathway blocks RNA virus to escape immune elimination.

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TRIM21 is a novel regulator of Par-4 in colon and pancreatic cancer cells

Cited by 49 publications

References 40 publications

Molecular Mechanisms by Which S100A4 Regulates the Migration and Invasion of PGCCs With Their Daughter Cells in Human Colorectal Cancer

Molecular Mechanisms by Which S100A4 Regulates the Migration and Invasion of PGCCs With Their Daughter Cells in Human Colorectal Cancer

Decreased expression of TRIM21 indicates unfavorable outcome and promotes cell growth in breast cancer

TRIM21 Promotes Innate Immune Response to RNA Viral Infection through Lys27-Linked Polyubiquitination of MAVS

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