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SOX2 expression is associated with a cancer stem cell state and down-regulation of CDX2 in colorectal cancer
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Kirurgi.
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2016 (Engelska)Ingår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 16, artikel-id 471Artikel i tidskrift (Refereegranskat) Published
Resurstyp
Text
Abstract [en]

Background: To improve current treatment strategies for patients with aggressive colorectal cancer (CRC), the molecular understanding of subgroups of CRC with poor prognosis is of vast importance. SOX2 positive tumors have been associated with a poor patient outcome, but the functional role of SOX2 in CRC patient prognosis is still unclear. Methods: An in vitro cell culture model expressing SOX2 was used to investigate the functional role of SOX2 in CRC. In vitro findings were verified using RNA from fresh frozen tumor tissue or immunohistochemistry on formalin fixed paraffin embedded (FFPE) tumor tissue from a cohort of 445 CRC patients. Results: Using our in vitro model, we found that SOX2 expressing cells displayed several characteristics of cancer stem cells; such as a decreased proliferative rate, a spheroid growth pattern, and increased expression of stem cell markers CD24 and CD44. Cells expressing SOX2 also showed down-regulated expression of the intestinal epithelial marker CDX2. We next evaluated CDX2 expression in our patient cohort. CDX2 down-regulation was more often found in right sided tumors of high grade and high stage. Furthermore, a decreased expression of CDX2 was closely linked to MSI, CIMP-high as well as BRAF mutated tumors. A decreased expression of CDX2 was also, in a stepwise manner, strongly correlated to a poor patient prognosis. When looking at SOX2 expression in relation to CDX2, we found that SOX2 expressing tumors more often displayed a down-regulated expression of CDX2. In addition, SOX2 expressing tumors with a down-regulated CDX2 expression had a worse patient prognosis compared to those with retained CDX2 expression. Conclusions: Our results indicate that SOX2 expression induces a cellular stem cell state in human CRC with a decreased expression of CDX2. Furthermore, a down-regulated expression of CDX2 results in a poor patient prognosis in CRC and at least part of the prognostic importance of SOX2 is mediated through CDX2 down-regulation.

Ort, förlag, år, upplaga, sidor
2016. Vol. 16, artikel-id 471
Nyckelord [en]
SOX2, CDX2, Colorectal cancer, Prognosis, Cancer stem cell
Nationell ämneskategori
Cell- och molekylärbiologi Cancer och onkologi
Identifikatorer
URN: urn:nbn:se:umu:diva-124507DOI: 10.1186/s12885-016-2509-5ISI: 000380091600001PubMedID: 27411517OAI: oai:DiVA.org:umu-124507DiVA, id: diva2:953888
Tillgänglig från: 2016-08-19 Skapad: 2016-08-15 Senast uppdaterad: 2018-06-07Bibliografiskt granskad
Ingår i avhandling
1. Molecular understanding of KRAS- and BRAF-mutated colorectal cancers
Öppna denna publikation i ny flik eller fönster >>Molecular understanding of KRAS- and BRAF-mutated colorectal cancers
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Colorectal cancer (CRC) is the third most commonly diagnosed malignancy in both men and women, and one of the leading causes of cancer-related deaths worldwide. One frequently mutated pathway involved in oncogenesis in CRC is the RAS/RAF/MAP kinase pathway. Oncogenic activation of KRAS and BRAF occur in 30‒40% and 5‒15% of all CRCs, respectively, and the mutations are mutually exclusive. Even though KRAS and BRAF are known to act in the same pathway, KRAS- and BRAF-mutated CRCs have different clinical and histopathological features. For example, BRAF mutation in CRC is tightly linked to microsatellite instability (MSI) and a CpG island methylator phenotype (CIMP), which is not seen in KRAS-mutated tumours. BRAF-mutated CRCs are also more often found in right-sided tumours. However, the underlying molecular reasons for these differences have not yet been defined.

The overall aim of this thesis was to investigate molecular differences between KRAS- and BRAF-mutated CRCs to understand how KRAS and BRAF mutations differentially affect tumour progression. We used an in vitro cell culture system to explore molecular differences between KRAS- and BRAF-mutated CRCs and verified our findings using CRC tissue specimens from the Colorectal Cancer in Umeå Study (CRUMS).

We found that BRAF mutation, but not KRAS mutation, was associated with expression of the stem cell factor SOX2. Furthermore, SOX2 was found to be correlated to a poor patient prognosis, especially in BRAF-mutated cancers. We further investigated the role of BRAF in regulation of SOX2 expression and found that SOX2 is at least partly regulated by BRAF in vitro. We continued by investigating the functional role of SOX2 in CRC and found that SOX2-expressing cells shared several characteristics with cancer stem cells, and also had down-regulated expression of the intestinal epithelial marker CDX2. There was a strong correlation between loss of CDX2 expression and poor patient prognosis, and patients with SOX2 expression were found to have a particularly poor prognosis when CDX2 levels were down-regulated. In conclusion, in these studies we identified a subgroup of BRAF-mutated CRCs with a particularly poor prognosis, and having a cancer stem cell-like appearance with increased expression of SOX2 and decreased expression of CDX2.

Tumour progression is regulated by interactions with cells of the immune system. We found that BRAF-mutated CRCs were more highly infiltrated by Th1 lymphocytes than BRAF wild-type tumours, while the opposite was true for KRAS-mutated CRCs. Interestingly, we found that part of this difference is probably caused by differences in secreted chemokines and cytokines between KRAS- and BRAF-mutated CRCs, stimulating different arms of the immune response.

Altered levels of expression of miRNAs have been seen in several malignancies, including CRC. We found that BRAF- and KRAS-mutated CRCs showed miRNA signatures different from those of wild-type CRCs, but the expression of miRNAs did not distinguish KRAS-mutated tumours from BRAF-mutated tumours.

In summary, our findings have revealed possible molecular differences between KRAS- and BRAF-mutated CRCs that may explain some of the differences in their clinical and histopathological behaviour.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, 2017. s. 44
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1885
Nyckelord
Colorectal cancer, BRAF, KRAS, SOX2, CDX2, cancer stem cell, Th1 lymphocytes, miRNA, prognosis
Nationell ämneskategori
Cancer och onkologi Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-133410 (URN)978-91-7601-677-0 (ISBN)
Disputation
2017-05-05, Hörsal E04, byggnad 6E, Norrlands universitetssjukhus, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2017-04-12 Skapad: 2017-04-10 Senast uppdaterad: 2018-06-09Bibliografiskt granskad

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