Change search
ReferencesLink to record
Permanent link

Direct link
Downregulation of SMG-1 in HPV-Positive Head and Neck Squamous Cell Carcinoma Due to Promoter Hypermethylation Correlates with Improved Survival
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
Show others and affiliations
2012 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 18, no 5, 1257-1267 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: Human papillomavirus (HPV) is linked with a subset of head and neck squamous cell carcinomas (HNSCC). HPV-positive HNSCCs show a better prognosis than HPV-negative HNSCCs, which may be explained by sensitivity of the HPV-positive HNSCCs to ionizing radiation (IR). Although the molecular mechanism behind sensitivity to IR in HPV-positive HNSCCs is unresolved, DNA damage response (DDR) might be a significant determinant of IR sensitivity. An important player in the DDR, SMG-1 (suppressor with morphogenetic effect on genitalia), is a potential tumor suppressor and may therefore be deregulated in cancer. No studies have yet been conducted linking defects in SMG-1 expression with cancer. We investigated whether deregulation of SMG-1 could be responsible for defects in the DDR in oropharyngeal HNSCC. Experimental Design: Expression and promoter methylation status of SMG-1 were investigated in HNSCCs. To identify a functional link between HPV infection and SMG-1, we transfected the HPV-negative cells with an E6/E7 expression construct. SMG-1 short hairpin RNAs were expressed in HPV-negative cells to estimate survival upon IR. Results: Forced E6/E7 expression in HPV-negative cells resulted in SMG-1 promoter hypermethylation and decreased SMG-1 expression. Due to promoter hypermethylation, HPV-positive HNSCC cells and tumors express SMG-1 at lower levels than HPV-negative SCCs. Depletion of SMG-1 in HPV-negative HNSCC cells resulted in increased radiation sensitivity, whereas SMG-1 overexpression protected HPV-positive tumor cells from irradiation. Conclusions: Levels of SMG-1 expression negatively correlated with HPV status in cancer cell lines and tumors. Diminished SMG-1 expression may contribute to the enhanced response to therapy exhibited by HPV-positive HNSCCs. 

Place, publisher, year, edition, pages
2012. Vol. 18, no 5, 1257-1267 p.
National Category
Microbiology Cancer and Oncology
URN: urn:nbn:se:su:diva-76991DOI: 10.1158/1078-0432.CCR-11-2058ISI: 000301040700010OAI: diva2:530279
7Available from: 2012-06-01 Created: 2012-05-28 Last updated: 2013-11-12Bibliographically approved
In thesis
1. Novel functions of SMG-1 in carcinogenesis
Open this publication in new window or tab >>Novel functions of SMG-1 in carcinogenesis
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Damage to DNA can cause mutations leading to cancer, and the DNA damage response (DDR), leading to transient cell-cycle arrest, DNA repair, senescence and apoptosis, plays a role in preventing tumor formation. At the same time, agents that damage DNA are used as anticancer therapy. The DDR has been extensively studied since the mid-nineties, when the genes of the major checkpoint kinases involved were cloned. Since then, quite a detailed model of the DDR has been worked out. According to the current model, the proximal stress-responsive kinases that are essential for the whole signaling cascade to function properly are ATM and ATR belonging to the family of phosphatidyl-inositol 3-kinase-related kinases (PIKKs). SMG-1 is the latest addition to this family, and accumulating evidence is pointing to its role in genome surveillance.

In Paper I, we showed that SMG-1 regulates the G1/S checkpoint in response to ionizing radiation (IR) by two mechanisms. In addition to regulating the p53/p21 pathway by phosphorylating p53 and thus regulating its stability and activity, we have demonstrated a novel role for SMG-1 in regulating cell cycle progression and tumor growth via the p53-independent pathway. We identified Cdc25A as a new SMG-1 substrate and found that SMG-1 suppresses CDK2 activity in response to DNA damage, as well as in unperturbed cells.

Head and neck squamous cell carcinoma (HNSCC) is divided into human papillomavirus (HPV)-positive and HPV-negative subgroups, of which HPV-positive cancers are sensitive to IR treatment and show a more favorable prognosis compared to HPV-negative HNSCCs.  In Paper II, for the first time, we have shown a link between defects in SMG-1 expression and cancer. We demonstrated that HPV-positive HNSCC cancer cell lines and tumors express SMG-1 at lower levels than HPV-negative HNSCCs due to promoter hypermethylation. We concluded that diminished SMG-1 levels may contribute to the enhanced response to radiation therapy exhibited by HPV-positive HNSCCs.  

Senescence and epithelial-mesenchymal transition (EMT) are both tightly linked to carcinogenesis. Oncogene-induced senescence (OIS) functions as a barrier against tumor progression, while EMT promotes tumor progression and metastasis. In Paper III, we identified previously unknown roles of SMG-1 in these two cellular processes. SMG-1 deficient cells failed to initiate the OIS program induced by activation of Ras. Downregulation of SMG-1 also induced morphologic and molecular changes consistent with EMT. We propose that, by regulating senescence and suppressing EMT, SMG-1 inhibits cancer progression. 

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2013. 47 p.
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Genetics
urn:nbn:se:su:diva-96037 (URN)978-91-7447-806-8 (ISBN)
Public defence
2013-12-06, William-Olssonsalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 13:00 (English)

At the time of the doctoral defence the following paper was unpublished and had a status as follows: Paper 3: Manuscript.

Available from: 2013-11-14 Created: 2013-11-08 Last updated: 2013-11-12Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Gubanova, Evgenia
By organisation
Department of Genetics, Microbiology and Toxicology
In the same journal
Clinical Cancer Research
MicrobiologyCancer and Oncology

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 293 hits
ReferencesLink to record
Permanent link

Direct link