<i>TRIM67</i> Promotes Non-Small Cell Lung Cancer Development by Positively Regulating the Notch Pathway through DLK1 Ubiquitination

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Abstract

Tripartite motif-containing 67 (TRIM67), a member of the TRIM protein family, is an E3 ubiquitin ligase. Our previous study revealed a relationship between TRIM67 expression and carcinogenesis, showing that TRIM67 expression is linked to p-TNM stage, lymph node metastasis, tumour size, cancer cell differentiation, and poor prognosis. Additionally, TRIM67 immunostaining results were associated with clinicopathological features. TRIM67 activated the Notch pathway in a favourable manner to enhance cell invasion, migration, and proliferation. Atypical ligand delta like non-canonical Notch ligand 1 (DLK1) inhibits the function of the Notch1 receptor, which in turn prevents activation of the Notch pathway. In addition, we investigated the mechanism by which TRIM67 influences the Notch pathway. We found that TRIM67 altered the behaviour of non-small cell lung cancer (NSCLC) cells by ubiquitinating DLK1 via its RING domain, which in turn activates the Notch pathway. Taken together, these findings indicate that TRIM67 may be involved in promoting the growth of NSCLC.

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Most cited references 33

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Global Cancer Incidence and Mortality Rates and Trends--An Update

L. A. Torre, R L Siegel, E Ward … (2016)

There are limited published data on recent cancer incidence and mortality trends worldwide. We used the International Agency for Research on Cancer's CANCERMondial clearinghouse to present age-standardized cancer incidence and death rates for 2003-2007. We also present trends in incidence through 2007 and mortality through 2012 for select countries from five continents. High-income countries (HIC) continue to have the highest incidence rates for all sites, as well as for lung, colorectal, breast, and prostate cancer, although some low- and middle-income countries (LMIC) now count among those with the highest rates. Mortality rates from these cancers are declining in many HICs while they are increasing in LMICs. LMICs have the highest rates of stomach, liver, esophageal, and cervical cancer. Although rates remain high in HICs, they are plateauing or decreasing for the most common cancers due to decreases in known risk factors, screening and early detection, and improved treatment (mortality only). In contrast, rates in several LMICs are increasing for these cancers due to increases in smoking, excess body weight, and physical inactivity. LMICs also have a disproportionate burden of infection-related cancers. Applied cancer control measures are needed to reduce rates in HICs and arrest the growing burden in LMICs.

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RING domain E3 ubiquitin ligases.

Raymond J Deshaies, Claudio A. P. Joazeiro (2009)

E3 ligases confer specificity to ubiquitination by recognizing target substrates and mediating transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to substrate. The activity of most E3s is specified by a RING domain, which binds to an E2 approximately ubiquitin thioester and activates discharge of its ubiquitin cargo. E2-E3 complexes can either monoubiquitinate a substrate lysine or synthesize polyubiquitin chains assembled via different lysine residues of ubiquitin. These modifications can have diverse effects on the substrate, ranging from proteasome-dependent proteolysis to modulation of protein function, structure, assembly, and/or localization. Not surprisingly, RING E3-mediated ubiquitination can be regulated in a number of ways. RING-based E3s are specified by over 600 human genes, surpassing the 518 protein kinase genes. Accordingly, RING E3s have been linked to the control of many cellular processes and to multiple human diseases. Despite their critical importance, our knowledge of the physiological partners, biological functions, substrates, and mechanism of action for most RING E3s remains at a rudimentary stage.

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Is Open Access

Progress and prospects of early detection in lung cancer

Sean Blandin Knight, Phil Crosbie, Haval Balata … (2017)

Lung cancer is the leading cause of cancer-related death in the world. It is broadly divided into small cell (SCLC, approx. 15% cases) and non-small cell lung cancer (NSCLC, approx. 85% cases). The main histological subtypes of NSCLC are adenocarcinoma and squamous cell carcinoma, with the presence of specific DNA mutations allowing further molecular stratification. If identified at an early stage, surgical resection of NSCLC offers a favourable prognosis, with published case series reporting 5-year survival rates of up to 70% for small, localized tumours (stage I). However, most patients (approx. 75%) have advanced disease at the time of diagnosis (stage III/IV) and despite significant developments in the oncological management of late stage lung cancer over recent years, survival remains poor. In 2014, the UK Office for National Statistics reported that patients diagnosed with distant metastatic disease (stage IV) had a 1-year survival rate of just 15–19% compared with 81–85% for stage I.

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Author and article information

Journal

Journal ID (nlm-ta): J Cancer

Journal ID (iso-abbrev): J Cancer

Journal ID (publisher-id): jca

Title: Journal of Cancer

Publisher: Ivyspring International Publisher (Sydney )

ISSN (Electronic): 1837-9664

Publication date Collection: 2024

Publication date (Electronic): 4 February 2024

Volume: 15

Issue: 7

Pages: 1870-1879

Affiliations

Department of Pathology, Lequn Branch, The First Hospital of Jilin University, Changchun, China.

Author notes

✉ Corresponding author: Tel: +86 17767727811; Fax: +86 84886631; Email: yafangliu@ 123456jlu.edu.cn ; Address: Department of Pathology, Lequn Branch, The First Hospital of Jilin University, No. 3302 Jilin Road, Jilin, Changchun 130000, China.

Competing Interests: The authors have declared that no competing interest exists.

Article

Publisher ID: jcav15p1870

DOI: 10.7150/jca.92723

PMC ID: 10905413

PubMed ID: 38434968

SO-VID: 1738d391-d0fe-4012-8270-dd5ebdba2aa3

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

TRIM67 Promotes Non-Small Cell Lung Cancer Development by Positively Regulating the Notch Pathway through DLK1 Ubiquitination

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Karger: Oncology

Most cited references 33

Global Cancer Incidence and Mortality Rates and Trends--An Update

RING domain E3 ubiquitin ligases.

Progress and prospects of early detection in lung cancer

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