High expression of TRIM11 correlates with poor prognosis in patients with hepatocellular carcinoma

doi:10.1016/j.clinre.2016.09.010

Clinics and Research in Hepatology and Gastroenterology

Volume 41, Issue 2, March 2017, Pages 190-196

https://doi.org/10.1016/j.clinre.2016.09.010 Get rights and content

Summary

Background

Tripartite Motif Containing 11 (TRIM11), a member of TRIM proteins is overexpressed in gliomas and lung cancer. However, the role of TRIM11 in hepatocellular carcinoma (HCC) is unknown.

Basic procedures

Herein, we aimed to investigate the expression and clinical significance role of TRIM11 in HCC.

Main finding

In this study, our data showed significant higher TRIM11 in HCC tissues (n = 117) than in the matched non-tumor liver (NTL) tissues (P < 0.01). In consistent with above data, we also found TRIM11 protein expression was significantly increased compared with the matched NTL (P < 0.01) by immunohistochemistry analysis. Additionally, our results showed that TRIM11 protein expression in HCC tissues was significantly associated with pathological grade (P < 0.01), tumor postoperative metastasis (P = 0.031), recurrence (P = 0.022), and serum a-fetoprotein (AFP) (P < 0.01). Moreover, patients’ survival was negatively correlated with TRIM11 protein expression. Furthermore, we found that TRIM11 protein was an independent prognostic factor for disease-free (P < 0.01) and overall survival (P < 0.01) in HCC patients.

Principal conclusions

Our data showed that TRIM11 expression was significantly elevated in HCC tissues. The overexpression of TRIM11 is closely associated with HCC progression and poor survival of the patients, indicating TRIM11 is a potential therapeutic target for HCC patients.

Section snippets

Background

Hepatocellular carcinoma (HCC) is considered as a major global health problem. HCC is the primary form of liver cancer and every year it causes half a million death, which makes it the third leading cause of cancer-related death [1]. HCC is the second most common malignancy in China and prevalent in Southeast Asia and sub-Saharan Africa, where hepatitis B virus is endemic which makes it geographically specific [2], [3]. In spite of recent advances in treatment of cancer, e.g., chemotherapy,

HCC tissue samples

Written informed consents were obtained from all patients participated in this study, in which all patients agreed that the medical information and tissue from hepatectomy will be used for this study. 117 tumors and matched adjacent non-tumor liver (NTL) were collected between July 2009 and March 2011 from HCC patients who underwent surgical resection at Anhui Provincial Hospital, Anhui Medical University. Pathological examinations were performed to confirm the histopathological diagnoses.

TRIM11 was highly expressed in HCC

It has been reported that TRIM11 mRNA level was elevated in lung cancer [17]. However, TRIM11 mRNA level in HCC has not been reported. In order to investigate the TRIM11 mRNA level in HCC patients, qRT-PCR assay was carried out in 117 pairs HCC and corresponding NTL tissues. Significantly higher (P < 0.01) TRIM11 mRNA level was found in HCC tissues compared with NTL tissues (Fig. 1A). High mRNA level is generally associated with high level of its encoded protein. In order to confirm the protein

Discussion

To the best of our knowledge, this is the first study investigating the expression and clinical significance role of TRIM11 in HCC. In this study, we used qRT-PCR and immunohistochemistry to assess TRIM11 expression at both mRNA and protein level in large number of HCC tissue and corresponding NLC samples. In agreement with previous study [17], we found significant higher TRIM11 expression in tumor tissue than matched adjacent non-tumorous tissue. Our findings suggest that TRIM11 play an

Funding

None.

Disclosure of interest

The authors declare that they have no competing interest.

References (23)

R. Lozano et al.
Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010
Lancet
(2012)
J. Bruix et al.
Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study
Eur J Cancer
(2013)
H. Ishikawa et al.
TRIM11 binds to and destabilizes a key component of the activator-mediated cofactor complex (ARC105) through the ubiquitin-proteasome system
FEBS Lett
(2006)
S.J. Hong et al.
Trim11 increases expression of dopamine beta-hydroxylase gene by interacting with Phox2b
Biochem Biophys Res Commun
(2008)
X. Huo et al.
Tripartite motif 16 inhibits epithelial-mesenchymal transition and metastasis by down-regulating sonic hedgehog pathway in non-small cell lung cancer cells
Biochem Biophys Res Commun
(2015)
X. Wang et al.
TRIM11 overexpression promotes proliferation, migration and invasion of lung cancer cells
J Exp Clin Cancer Res
(2016)
E.N. Debruyne et al.
Diagnosing and monitoring hepatocellular carcinoma with alpha-fetoprotein: new aspects and applications
Clin Chim Acta
(2008)
R. Siegel et al.
Cancer statistics, 2013
CA Cancer J Clin
(2013)
I. Rapti et al.
Risk for hepatocellular carcinoma in the course of chronic hepatitis B virus infection and the protective effect of therapy with nucleos(t)ide analogues
World J Hepatol
(2015)
M. Maluccio et al.
Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma
CA Cancer J Clin
(2012)

A.X. Zhu et al.

HCC and angiogenesis: possible targets and future directions

Nat Rev Clin Oncol

(2011)

Cited by (26)

Deciphering roles of TRIMs as promising targets in hepatocellular carcinoma: current advances and future directions
2023, Biomedicine and Pharmacotherapy
Tripartite motif (TRIM) family is assigned to RING-finger-containing ligases harboring the largest number of proteins in E3 ubiquitin ligating enzymes. E3 ubiquitin ligases target the specific substrate for proteasomal degradation via the ubiquitin–proteasome system (UPS), which seems to be a more effective and direct strategy for tumor therapy. Recent advances have demonstrated that TRIM genes associate with the occurrence and progression of hepatocellular carcinoma (HCC). TRIMs trigger or inhibit multiple biological activities like proliferation, apoptosis, metastasis, ferroptosis and autophagy in HCC dependent on its highly conserved yet diverse structures. Remarkably, autophagy is another proteolytic pathway for intracellular protein degradation and TRIM proteins may help to delineate the interaction between the two proteolytic systems. In depth research on the precise molecular mechanisms of TRIM family will allow for targeting TRIM in HCC treatment. We also highlight several potential directions warranted further development associated with TRIM family to provide bright insight into its translational values in hepatocellular carcinoma.
Gene fusions in superficial mesenchymal neoplasms: Emerging entities and useful diagnostic adjuncts
2023, Seminars in Diagnostic Pathology
Cutaneous mesenchymal neoplasms are diagnostically challenging because of their overlapping morphology, and, often, the limited tissue in skin biopsy specimens. Molecular and cytogenetic techniques have identified characteristic gene fusions in many of these tumor types, findings that have expanded our understanding of disease pathogenesis and motivated development of useful ancillary diagnostic tools. Here, we provide an update of new findings in tumor types that can occur in the skin and superficial subcutis, including dermatofibrosarcoma protuberans, benign fibrous histiocytoma, epithelioid fibrous histiocytoma, angiomatoid fibrous histiocytoma, glomus tumor, myopericytoma/myofibroma, non-neural granular cell tumor, CIC-rearranged sarcoma, hybrid schwannoma/perineurioma, and clear cell sarcoma. We also discuss recently described and emerging tumor types that can occur in superficial locations and that harbor gene fusions, including nested glomoid neoplasm with GLI1 alterations, clear cell tumor with melanocytic differentiation and ACTIN::MITF translocation, melanocytic tumor with CRTC1::TRIM11 fusion, EWSR1::SMAD3-rearranged fibroblastic tumor, PLAG1-rearranged fibroblastic tumor, and superficial ALK-rearranged myxoid spindle cell neoplasm. When possible, we discuss how fusion events mediate the pathogenesis of these tumor types, and we also discuss the related diagnostic and therapeutic implications of these events.
The translational values of TRIM family in pan-cancers: From functions and mechanisms to clinics
2021, Pharmacology and Therapeutics
Citation Excerpt :
Thirty studies have discussed the role of TRIM in breast cancer. TRIM11 (L. Chen, Li, Qian, Ge, & Xu, 2017; X. Dai, Geng, Li, & Liu, 2019), TRIM14 (G. Hu, Pen, & Wang, 2019), TRIM25 (Ikeda, Orimo, Higashi, Muramatsu, & Inoue, 2000; Suzuki et al., 2005; Urano et al., 2002; Z. Wang, Tong, et al., 2019), TRIM27 (Townson, Kang, Lee, & Oesterreich, 2006), TRIM28 (Addison et al., 2015; Czerwinska et al., 2017; Damineni et al., 2017; J. Li et al., 2017; C. Wei et al., 2016), TRIM37 (Bhatnagar et al., 2014; X. Hu et al., 2019; Przanowski et al., 2020; Yeow et al., 2020), TRIM44 (Kawabata et al., 2017), TRIM47 (Y. Wang, Liu, Xie, & Lu, 2020), TRIM59 (Y. Liu et al., 2018; P. Tan, Ye, et al., 2018), and TRIM63 (K. Li et al., 2019) act as oncogenic proteins, and were all found to be overexpressed in breast cancer. The ability to degrade misfolded proteins is enhanced in the process of tumorigenesis, and decreased in tumor differentiation (F. Huang, Wang, & Wang, 2018).
Cancer is the second leading cause of human death across the world. Tripartite motif (TRIM) family, with E3 ubiquitin ligase activities in majority of its members, is reported to be involved in multiple cellular processes and signaling pathways. TRIM proteins have critical effects in the regulation of biological behaviors of cancer cells. Here, we discussed the current understanding of the molecular mechanism of TRIM proteins regulation of cancer cells. We also comprehensively reviewed published studies on TRIM family members as oncogenes or tumor suppressors in the oncogenesis, development, and progression of a variety of types of human cancers. Finally, we highlighted that certain TRIM family members are potential molecular biomarkers for cancer diagnosis and prognosis, and potential therapeutic targets.
miR-5193, regulated by FUT1, suppresses proliferation and migration of ovarian cancer cells by targeting TRIM11
2020, Pathology Research and Practice
Citation Excerpt :
TRIM11, a member of TRIM protein family, has attracted much attention since its roles in nervous system function were revealed [28,12]. Recently, TRIM11 was confirmed to exert an oncogenic function in the tumorigenesis of certain cancer diseases, including hepatocellular carcinoma [2], breast cancer [27] and ovarian cancer [3]. Pan Y et al. have demonstrated that TRIM11 expression was down-regulated by miR-5193 in human prostate cancer [24].
Ovarian cancer is the most lethal gynecological malignancy worldwide. A better understanding of the pathogenesis of ovarian cancer may help to improve the overall survival. Our previous studies have demonstrated that alpha-(1,2)-fucosyltransferase 1 (FUT1) is an oncogenic glycogene in ovarian cancer. However, the underlying mechanism is not fully clarified. In this study, we identified a microRNA as an important downstream regulator for the carcinogenic effect of FUT1 in ovarian cancer. miR-5193 was found down-regulated in ovarian cancer cells, FUT1-overexpression ovarian cancer cells and ovarian tumor samples. MTT, flow cytometry and Transwell assays demonstrated that miR-5193 inhibited the proliferation and migration, and induced the cell cycle arrest and apoptosis of ovarian cancer cells. Real-time PCR and western blot assays showed that miR-5193 downregulated the expression of TRIM11 and upregulated the expression of p53 and p21. Dual luciferase reporter assay indicated that TRIM11 was a direct target of miR‑5193. Rescue experiments confirmed that miR-5193 functioned in ovarian cancer cells by directly targeting TRIM11. Moreover, transfection with miR-5193 mimic in FUT1-overexpression ovarian cancer cells reversed the carcinogenic effect of FUT1. Taken together, our results suggest that miR-5193 is an essential suppressor of human ovarian cancer development, and is an important downstream regulator regarding the carcinogenesis of FUT1 in ovarian cancer.
TRIM11 promotes breast cancer cell proliferation by stabilizing estrogen receptor α
2020, Neoplasia (United States)
Citation Excerpt :
TRIM11 is an E3 ubiquitin ligase and belongs to the TRIM family. The oncogene role of TRIM11 has been reported in a variety of human cancers, including glioma, lung cancer and hepatocellular carcinoma cancer [11–14]. In breast cancer, TRIM11 is also a crucial proto-oncogene, depletion of TRIM11 dramatically reduced the proliferation in different types of breast cancer cells [31].
Breast cancer is the most commonly diagnosed malignancy in female worldwide, over 70% of which are estrogen receptor α (ERα) positive. ERα has a crucial role in the initiation and progression of breast cancer and is an indicator of endocrine therapy, while endocrine resistance is an urgent problem in ER-positive breast cancer patients. In the present study, we identify a novel E3 ubiquitin ligase TRIM11 function to facilitate ERα signaling. TRIM11 is overexpressed in human breast cancer, and associates with poor prognosis. The protein level of TRIM11 is highly correlated with ERα. RNA-seq results suggest that ERα signaling may be an underlying target of TRIM11. Depletion of TRIM11 in breast cancer cells significantly decreases cell proliferation and migration. And the suppression effects can be reversed by overexpressing ERα. In addition, ERα protein level, ERα target genes expression and estrogen response element activity are also dramatically decreased by TRIM11 depletion. Further mechanistic analysis indicates that the RING domain of TRIM11 interacted with the N terminal of ERα in the cytoplasm and promotes its mono-ubiquitination, thus enhances ERα protein stability. Our study describes TRIM11 as a modulating factor of ERα and increases ERα stability via mono-ubiquitination. TRIM11 could be a promising therapeutic target for breast cancer treatment.
TRIM8: a double-edged sword in glioblastoma with the power to heal or hurt
2023, Cellular and Molecular Biology Letters

View all citing articles on Scopus

View full text

Original articleHigh expression of TRIM11 correlates with poor prognosis in patients with hepatocellular carcinoma

Summary

Background

Basic procedures

Main finding

Principal conclusions

Section snippets

Background

HCC tissue samples

TRIM11 was highly expressed in HCC

Discussion

Funding

Disclosure of interest

Lancet

Eur J Cancer

FEBS Lett

Biochem Biophys Res Commun

Biochem Biophys Res Commun

J Exp Clin Cancer Res

Clin Chim Acta

Cancer statistics, 2013

CA Cancer J Clin

Risk for hepatocellular carcinoma in the course of chronic hepatitis B virus infection and the protective effect of therapy with nucleos(t)ide analogues

World J Hepatol

Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma

CA Cancer J Clin

HCC and angiogenesis: possible targets and future directions

Nat Rev Clin Oncol

Original article
High expression of TRIM11 correlates with poor prognosis in patients with hepatocellular carcinoma