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Gnosa, Sebastian
Publications (8 of 8) Show all publications
Gnosa, S., Capodanno, A., Dahl Ejby Jensen, L. & Sun, X.-F. (2016). AEG-1 knockdown in colon cancer cell lines inhibits radiation-enhanced migration and invasion in vitro and in a novel in vivo zebrafish model. OncoTarget, 7(49), 81634-81644
Open this publication in new window or tab >>AEG-1 knockdown in colon cancer cell lines inhibits radiation-enhanced migration and invasion in vitro and in a novel in vivo zebrafish model
2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 49, p. 81634-81644Article in journal (Refereed) Published
Abstract [en]

Background Radiotherapy is a well-established anti-cancer treatment. Although radiotherapy has been shown to significantly decrease the local relapse in rectal cancer patients, the rate of distant metastasis is still very high. Several studies have shown that radiation enhances migration and invasion both in vitro and in vivo. The aim of this study was to evaluate whether AEG-1 is involved in radiation-enhanced migration and invasion in vitro and in a novel in vivo zebrafish model.

Materials and Methods We evaluated the involvement of AEG-1 in migration and invasion and radiation-enhanced migration and invasion by Boyden chamber assay in three colon cancer cell lines and respective AEG-1 knockdown cell lines. Furthermore, we injected the cells in zebrafish embryos and evaluated the amount of disseminated cells into the tail.

Results Migration and invasion was decreased in all the AEG-1 knockdown cell lines. Furthermore, radiation enhanced migration and invasion, while AEG-1 knockdown could abolish this effect. The results from the zebrafish model confirmed the results obtained in vitro. MMP-9 secretion and expression were decreased in AEG-1 knockdown cells.

Conclusion Our results demonstrate that AEG-1 knockdown inhibits migration and invasion, as well as radiation-enhanced migration and invasion. We speculate that this is done via the downregulation of the intrinsic or radiation-enhanced MMP-9 expression. The zebrafish model can be used to study early events in radiation-enhanced invasion.

Place, publisher, year, edition, pages
Impact Journals, 2016
Keywords
AEG-1, MTDH, LYRIC, Colon cancer, Zebrafish, Transwell migration and invasion, Radiation
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-121866 (URN)10.18632/oncotarget.13155 (DOI)000389877500121 ()27835571 (PubMedID)
Note

The previous status of this publication was manuscript

Funding agencies: Swedish Cancer Foundation; Swedish Research Council; Health Research Council in South-East Sweden; Onkologiska klinikernas i Linkoping

Available from: 2015-10-12 Created: 2015-10-12 Last updated: 2017-12-01Bibliographically approved
Gnosa, S., Ticha, I., Haapaniemi, S. & Sun, X.-F. (2016). MTDH genetic variants in colorectal cancer patients. Scientific Reports, 6
Open this publication in new window or tab >>MTDH genetic variants in colorectal cancer patients
2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6Article in journal (Refereed) Published
Abstract [en]

Colorectal cancer (CRC) is the second most common cancer worldwide and accounts for around 8.5% of all cancer related death. The colorectal carcinogenesis is a complex process of genetic alterations. For better prognosis it is very important to understand the composition of genetic alterations in a tumor. Astrocyte elevated gene-1 (AEG-1) has been shown to be overexpressed in CRC and had prognostic significance. The aim of this study was to determine the frequency and the spectrum of MTDH variants, and their relationship to clinicopathological variables in CRC patients. The study included tumors from 356 unselected CRC patients. Mutation analysis of the MTDH gene, including coding region and adjacent intronic sequences, was performed by direct DNA sequencing. We detected 42 intronic variants, whereby 25 were novel. Furthermore, we found eight exonic variants of which four, one missense (c.977C>G) and three frameshift mutations (c.533delA, c.1731delA, c.1340dupA), were novel. In silico prediction analyses revealed that four variants c.232G>T, c.533delA, c.1340dupA and c.1731delA were deleterious. There were no correlations between the MTDH variants and tumor stage, differentiation or patient survival. The detection of pathogenic mutations and alterations in functional protein domains suggest their involvement in tumorigenesis, although none of the variants had prognostic potential.

Place, publisher, year, edition, pages
Nature Publishing Group, 2016
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-121865 (URN)10.1038/srep23163 (DOI)000372164500001 ()
Note

Funding agencies:  Swedish Cancer Foundation; Swedish Research Council, and the Health Research Council in South-East Sweden; Ministry of Health, Czech Republic [RVO 64165]

Vid tiden för disputation förelåg publikationen som manuskript

Available from: 2015-10-12 Created: 2015-10-12 Last updated: 2017-12-01Bibliographically approved
Gnosa, S. (2015). Astrocyte elevated gene-1 in relation to colorectal cancer development and radiotherapy response. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Astrocyte elevated gene-1 in relation to colorectal cancer development and radiotherapy response
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The incidence and death rate for colorectal cancer (CRC) decreased during the last decades as a result of improved diagnosis and treatment. However, CRC is still the third most common cancer in the world, and is responsible for about 700 000 deaths per year worldwide. Therefore, it is important to understand the mechanisms of the disease, and to find molecular markers in order to further improve prognosis, and to develop new treatment strategies. Astrocyte elevated gene-1 (AEG-1), encoded by the MTDH gene, is upregulated in a variety of cancers. AEG-1 is involved in cell survival, proliferation, migration, invasion, metastasis,  angiogenesis, and apoptosis.

The aim of this thesis was to investigate the role of AEG-1 in CRC development and the impact of AEG-1 on the response of radiation treatment. The AEG-1 expression, analysed in different CRC patient cohorts in paper I and III, was increased in the tumour tissue compared with the normal mucosa, and higher in the lymph node and liver metastases. Expression analyses in normal and cancer cell lines confirmed these results. In paper II, sequencing of the complete coding sequence of the MTDH gene in 356 patients revealed 50 single nucleotide variants of which 29 were novel. Eight exonic variants were detected, including three frameshift variants which were probably pathogenic, and two missense variants located in functional protein regions. There was no correlation of the MTDH variants or AEG-1 expression with the patient survival. In paper III, we also investigated the impact of AEG-1 on the response to radiation treatment. AEG-1 knockdown decreased the cellular survival upon radiation in several colon cancer cell lines. The AEG-1 expression was furthermore analysed in patients, which were randomised to either surgery alone or preoperative radiotherapy (RT), followed by surgery. The rectal cancer patients with high AEG-1 expression treated with RT had a significantly higher risk of developing distant recurrence and had a worse disease free survival, likely due to the metastasis promoting properties of AEG-1. In paper IV, the impact of AEG-1 knockdown and radiation on migration and invasion was analysed in colon cancer cell lines in vitro  and in a novel zebrafish model in vivo. AEG-1 knockdown decreased migration and invasion, and radiation-enhanced migration and invasion in the cell lines tested.

In conclusion, our data suggest that AEG-1 is involved in CRC development, while MTDH gene variants probably not have a high clinical importance in CRC. Furthermore, AEG-1 is a promising radiosensitising target and a valuable prognostic marker in CRC. We further showed that AEG-1 knockdown inhibits migration and invasion, as well as radiation-enhanced cell migration and invasion.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. p. 84
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1476
National Category
Cancer and Oncology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:liu:diva-121868 (URN)10.3384/diss.diva-121868 (DOI)978-91-7685-970-4 (ISBN)
Public defence
2015-11-13, Berzeliussalen, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2015-10-12 Created: 2015-10-12 Last updated: 2019-11-15Bibliographically approved
Gnosa, S., Zhang, H., Brodin Patcha, V., Carstensen, J., Adell, G. & Sun, X.-F. (2014). AEG-1 expression is an independent prognostic factor in rectal cancer patients with preoperative radiotherapy: a study in a Swedish clinical trial. British Journal of Cancer, 111(1), 166-173
Open this publication in new window or tab >>AEG-1 expression is an independent prognostic factor in rectal cancer patients with preoperative radiotherapy: a study in a Swedish clinical trial
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2014 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 111, no 1, p. 166-173Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

Preoperative radiotherapy (RT) is widely used to downstage rectal tumours, but the rate of recurrence varies significantly. Therefore, new biomarkers are needed for better treatment and prognosis. It has been shown that astrocyte elevated gene-1 (AEG-1) is a key mediator of migration, invasion, and treatment resistance. Our aim was to analyse the AEG-1 expression in relation to RT in rectal cancer patients and to test its radiosensitising properties.

METHODS:

The AEG-1 expression was examined by immunohistochemistry in 158 patients from the Swedish clinical trial of RT. Furthermore, we inhibited the AEG-1 expression by siRNA in five colon cancer cell lines and measured the survival after irradiation by colony-forming assay.

RESULTS:

The AEG-1 expression was increased in the primary tumours compared with the normal mucosa independently of the RT (P<0.01). High AEG-1 expression in the primary tumour of the patients treated with RT correlated independently with higher risk of distant recurrence (P=0.009) and worse disease-free survival (P=0.007). Downregulation of AEG-1 revealed a decreased survival after radiation in radioresistant colon cancer cell lines.

CONCLUSIONS:

The AEG-1 expression was independently related to distant recurrence and disease-free survival in rectal cancer patients with RT and could therefore be a marker to discriminate patients for distant relapse.

Place, publisher, year, edition, pages
Nature Publishing Group, 2014
Keywords
MTDH; astrocyte elevated gene-1; distant recurrence; disease-free survival
National Category
Clinical Medicine Basic Medicine
Identifiers
urn:nbn:se:liu:diva-109376 (URN)10.1038/bjc.2014.250 (DOI)000339163300020 ()24874474 (PubMedID)
Available from: 2014-08-15 Created: 2014-08-15 Last updated: 2018-01-11Bibliographically approved
Pathak, S., Zhang, H., Gnosa, S., Kumar Nandy, S., Adell, G., Holmlund, B. & Sun, X.-F. (2014). Tafazzin protein expression is associated with tumorigenesis and radiation response in rectal cancer: a study of Swedish clinical trial on preoperative radiotherapy.. PLoS ONE, 9(5), e98317
Open this publication in new window or tab >>Tafazzin protein expression is associated with tumorigenesis and radiation response in rectal cancer: a study of Swedish clinical trial on preoperative radiotherapy.
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 5, p. e98317-Article in journal (Refereed) Published
Abstract [en]

Background

Tafazzin (TAZ), a transmembrane protein contributes in mitochondrial structural and functional modifications through cardiolipin remodeling. TAZ mutations are associated with several diseases, but studies on the role of TAZ protein in carcinogenesis and radiotherapy (RT) response is lacking. Therefore we investigated the TAZ expression in rectal cancer, and its correlation with RT, clinicopathological and biological variables in the patients participating in a clinical trial of preoperative RT.

Methods

140 rectal cancer patients were included in this study, of which 65 received RT before surgery and the rest underwent surgery alone. TAZ expression was determined by immunohistochemistry in primary cancer, distant, adjacent normal mucosa and lymph node metastasis. In-silico protein-protein interaction analysis was performed to study the predictive functional interaction of TAZ with other oncoproteins.

Results

TAZ showed stronger expression in primary cancer and lymph node metastasis compared to distant or adjacent normal mucosa in both non-RT and RT patients. Strong TAZ expression was significantly higher in stages I-III and non-mucinious cancer of non-RT patients. In RT patients, strong TAZ expression in biopsy was related to distant recurrence, independent of gender, age, stages and grade (p = 0.043, HR, 6.160, 95% CI, 1.063–35.704). In silico protein-protein interaction study demonstrated that TAZ was positively related to oncoproteins, Livin, MAC30 and FXYD-3.

Conclusions

Strong expression of TAZ protein seems to be related to rectal cancer development and RT response, it can be a predictive biomarker of distant recurrence in patients with preoperative RT.

Place, publisher, year, edition, pages
PLoS, 2014
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-107922 (URN)10.1371/journal.pone.0098317 (DOI)000336839400065 ()
Available from: 2014-06-23 Created: 2014-06-23 Last updated: 2018-01-11Bibliographically approved
Ticha, I., Gnosa, S., Lindblom, A., Liu, T. & Sun, X.-F. (2013). Variants of the PPARD Gene and Their Clinicopathological Significance in Colorectal Cancer. PLoS ONE, 8(12), 83952
Open this publication in new window or tab >>Variants of the PPARD Gene and Their Clinicopathological Significance in Colorectal Cancer
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. 83952-Article in journal (Refereed) Published
Abstract [en]

Background: Peroxisome proliferator-activated receptor delta (PPARD) is nuclear hormone receptor involved in colorectal cancer (CRC) differentiation and progression. The purpose of this study was to determine prevalence and spectrum of variants in the PPARD gene in CRC, and their contribution to clinicopathological endpoints. Methods and Findings: Direct sequencing of the PPARD gene was performed in 303 primary tumors, in blood samples from 50 patients with greater than= 3 affected first-degree relatives, 50 patients with 2 affected first-degree relatives, 50 sporadic patients, 360 healthy controls, and in 6 colon cancer cell lines. Mutation analysis revealed 22 different transversions, 7 of them were novel. Three of all variants were somatic (c. 548Agreater thanG, p.Y183C, c.425-9Cgreater thanT, and c.628-16Ggreater thanA). Two missense mutations (p.Y183C and p.R258Q) were pathogenic using in silico predictive program. Five recurrent variants were detected in/adjacent to the exons 4 (c.1-87Tgreater thanC, c.1-67Ggreater thanA, c.130+3Ggreater thanA, and c.1-101-8Cgreater thanT) and exon 7 (c.489Tgreater thanC). Variant c.489C/C detected in tumors was correlated to worse differentiation (P=0.0397). Conclusions: We found 7 novel variants among 22 inherited or acquired PPARD variants. Somatic and/or missense variants detected in CRC patients are rare but indicate the clinical importance of the PPARD gene.

Place, publisher, year, edition, pages
Public Library of Science, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-104127 (URN)10.1371/journal.pone.0083952 (DOI)000329325200151 ()
Available from: 2014-02-07 Created: 2014-02-07 Last updated: 2017-12-06
Gnosa, S., Shen, Y. M., Wang, C.-J., Zhang, H., Stratmann, J., Sun, X.-F. & Arbman, G. (2012). Expression of AEG-1 mRNA and protein in colorectal cancer patients and colon cancer cell lines. Journal of Translational Medicine, 10(109)
Open this publication in new window or tab >>Expression of AEG-1 mRNA and protein in colorectal cancer patients and colon cancer cell lines
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2012 (English)In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 10, no 109Article in journal (Refereed) Published
Abstract [en]

Background: Astrocyte elevated gene 1 (AEG-1), an important oncogene, has been shown to be overexpressed in several types of cancers. In colorectal cancer (CRC), the protein level of AEG-1 is up-regulated in tumour tissue compared to normal mucosa, showing prognostic significance. Since little is known about the transcriptional level of AEG-1 expression and its biological pathway in CRC the aim of the present study was to examine the relationship of AEG-1 mRNA expression, the protein level and clinicopathological variables as well as its biology pathway in CRC. less thanbrgreater than less thanbrgreater thanMaterial and methods: The mRNA expression of AEG-1 was analysed by qPCR in fresh frozen patient samples including 156 primary tumours, along with the corresponding normal mucosa, and in five colon cancer cell lines, SW480, SW620, KM12C, KM12SM and KM12L4a. AEG-1 protein expression was investigated by immunohistochemistry in paraffin-embedded materials from 74 distant normal mucosa, 107 adjacent mucosa, 158 primary tumour, 35 lymph node metastasis and 9 liver metastasis samples. In addition, the AEG-1 protein expression was elucidated in the cell lines by Western blot. less thanbrgreater than less thanbrgreater thanResults: The lymph node metastatic cell line SW620 had a significantly higher AEG-1 mRNA (0.27 +/- 0.02) expression compared to the primary tumour cell line SW480 (0.17 +/- 0.04, p = 0.026). AEG-1 expression at the mRNA level and/or the protein level was significantly up-regulated gradually from normal mucosa to primary CRC, and then to lymph node metastasis and finally to liver metastasis (p andlt; 0.05). There were significant associations of AEG-1 mRNA expression with tumour location (p = 0.047), as well as mRNA and protein expression with the tumour stage (p andlt; 0.03). Furthermore AEG-1 protein expression was positively related to biological variables including NF-kappa B, p73, Rad50 and apoptosis (p andlt; 0.05). less thanbrgreater than less thanbrgreater thanConclusion: AEG-1 is up-regulated, at the mRNA and the protein level, during CRC development and aggressiveness, and is related to tumour location and stage. It may play its role in CRC through the NF-kappa B signaling pathway.

Place, publisher, year, edition, pages
BioMed Central, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-80795 (URN)10.1186/1479-5876-10-109 (DOI)000307018200001 ()
Note

Funding Agencies|Swedish Cancer Foundation||Swedish Research Council||Health Research Council in the South-East of Sweden||

Available from: 2012-08-30 Created: 2012-08-30 Last updated: 2018-10-08
Stratmann, J., Wang, C., Gnosa, S., Wallin, Å., Hinselwood, D., Sun, X.-F. & Zhang, H. (2011). Dicer and miRNA in relation to clinicopathological variables in colorectal cancer patients. BMC Cancer, 11(345)
Open this publication in new window or tab >>Dicer and miRNA in relation to clinicopathological variables in colorectal cancer patients
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2011 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 11, no 345Article in journal (Refereed) Published
Abstract [en]

Background: Dicer is aberrantly expressed in several types of cancers. Applying real-time PCR, we detected the expression of Dicer mRNA in normal mucosa (n = 162), primary colorectal cancer (CRC) (n = 162) and liver metastasis (n = 37), and analysed the relationship between Dicer expression and clinicopathological features. We also correlated the expression of Dicer mRNA to the miRNA expression of miR-141, miR-200a, miR-200b, mir-200c and miR-429 in liver metastases. less thanbrgreater than less thanbrgreater thanMethods: RT-PCR and qPCR were used to analyse the Dicer expression in normal mucosa, primary tumour and liver metastasis by using the High Capacity cDNA Reverse Transcription Kit and TaqMan (TM)(R) Gene Expression assays for Dicer and GAPDH. RT-PCR and qPCR were used to detect miRNA expression in liver metastases by utilizing TaqMan (R) MicroRNA Reverse Transcription Kit and TaqMan (R) miRNA Assays. Statistical analyses were performed with STATISTICA. less thanbrgreater than less thanbrgreater thanResults: Dicer expression in rectal cancer (3.146 +/- 0.953) was higher than in colon cancer (2.703 +/- 1.204, P = 0.018). Furthermore the Dicer expression was increased in primary tumours (3.146 +/- 0.952) in comparison to that in normal mucosa from rectal cancer patients (2.816 +/- 1.009, P = 0.034) but this is not evident in colon cancer patients. Dicer expression in liver metastases was decreased in comparison to that of either normal mucosa or primary tumour in both colon and rectal cancers (P andlt; 0.05). Patients with a high Dicer expression in normal mucosa had a worse prognosis compared to those with a low Dicer expression, independently of gender, age, tumour site, stage and differentiation (P andlt; 0.001, RR 3.682, 95% CI 1.749 - 7.750). In liver metastases, Dicer was positively related to miR-141 (R = 0.419, P = 0.015). less thanbrgreater than less thanbrgreater thanConclusion: Dicer is up-regulated in the early development of rectal cancers. An increased expression of Dicer mRNA in normal mucosa from CRC patients is significantly related to poor survival independently of gender, age, tumour site, stage and differentiation.

Place, publisher, year, edition, pages
BioMed Central, 2011
Keywords
CRC, Dicer, miRNAs, Prognosis, qPCR
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-70750 (URN)10.1186/1471-2407-11-345 (DOI)000294408000001 ()
Note
Funding Agencies|Swedish Cancer Foundation||Swedish Research Council||Health Research Council in the South-East of Sweden||Available from: 2011-09-16 Created: 2011-09-16 Last updated: 2017-12-08
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