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Sox2 is associated with cancer stem-like properties in colorectal cancer.

ABSTRACT: Sox2 is known as the undifferentiated cell marker. Recent studies have shown that Sox2 may also be involved in the maintenance of cancer stem cells (CSCs) in skin and bladder cancers. In this study, we aimed to clarify the role of Sox2 in colorectal CSCs. Sox2 expression was measured in colon cancer cells and colorectal clinical samples by qRT-PCR and western blot analysis. To visualize the active Sox2 mRNA production, we generated a Sox2 promoter-dependent DsRed fluorescence emission system. Colon cancer cell lines and colorectal tumor tissues generally expressed the Sox2 protein. Knockdown of Sox2 by siRNA led to increased proliferative activity in Caco2 cells. Kaplan-Meier survival curves showed that the group with high Sox2 mRNA expression had a worse prognosis for relapse-free survival (RFS) than the low expression group (P?=?0.045, median follow-up 60.0 months). Time-lapse image analysis revealed that most DsRed⁺ cells exhibited typical asymmetric cell division and had higher CSC marker expressions. The DsRed⁺ cells exhibited chemoresistance and they grew slower in vitro, yet they established rather larger tumors in vivo. Our data suggest that Sox2 may be a potential biomarker for colorectal CSCs.

SUBMITTER: Takeda K

PROVIDER: S-EPMC6281572 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Sox2 is associated with cancer stem-like properties in colorectal cancer.

Takeda Koki K Mizushima Tsunekazu T Yokoyama Yuhki Y Hirose Haruka H Wu Xin X Qian Yamin Y Ikehata Katsuya K Miyoshi Norikatsu N Takahashi Hidekazu H Haraguchi Naotsugu N Hata Taishi T Matsuda Chu C Doki Yuichiro Y Mori Masaki M Yamamoto Hirofumi H

Scientific reports 20181205 1

Sox2 is known as the undifferentiated cell marker. Recent studies have shown that Sox2 may also be involved in the maintenance of cancer stem cells (CSCs) in skin and bladder cancers. In this study, we aimed to clarify the role of Sox2 in colorectal CSCs. Sox2 expression was measured in colon cancer cells and colorectal clinical samples by qRT-PCR and western blot analysis. To visualize the active Sox2 mRNA production, we generated a Sox2 promoter-dependent DsRed fluorescence emission system. Co ...[more]

PMID: 30518951

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Project description:BackgroundTransmembrane serine protease 4 (TMPRSS4) is a cell surface-anchored serine protease. Elevated expression of TMPRSS4 correlates with poor prognosis in colorectal cancer, gastric cancer, prostate cancer, non-small cell lung cancer, and other cancers. Previously, we demonstrated that TMPRSS4 promotes invasion and proliferation of prostate cancer cells. Here, we investigated whether TMPRSS4 confers cancer stem-like properties to prostate cancer cells and characterized the underlying mechanisms.MethodsAcquisition of cancer stem-like properties by TMPRSS4 was examined by monitoring anchorage-independent growth, tumorsphere formation, aldehyde dehydrogenase (ALDH) activation, and resistance to anoikis and drugs in vitro and in an early metastasis model in vivo. The underlying molecular mechanisms were evaluated, focusing on stemness-related factors regulated by epithelial-mesenchymal transition (EMT)-inducing transcription factors. Clinical expression and significance of TMPRSS4 and stemness-associated factors were explored by analyzing datasets from The Cancer Genome Atlas (TCGA).ResultsTMPRSS4 promoted anchorage-independent growth, ALDH activation, tumorsphere formation, and therapeutic resistance of prostate cancer cells. In addition, TMPRSS4 promoted resistance to anoikis, thereby increasing survival of circulating tumor cells and promoting early metastasis. These features were accompanied by upregulation of stemness-related factors such as SOX2, BMI1, and CD133. SLUG and TWIST1, master EMT-inducing transcription factors, made essential contributions to TMPRSS4-mediated cancer stem cell (CSC) features through upregulation of SOX2. SLUG stabilized SOX2 via preventing proteasomal degradation through its interaction with SOX2, while TWIST1 upregulated transcription of SOX2 by interacting with the proximal E-box element in the SOX2 promoter. Clinical data showed that TMPRSS4 expression correlated with the levels of SOX2, PROM1, SNAI2, and TWIST1. Expression of SOX2 was positively correlated with that of TWIST1, but not with other EMT-inducing transcription factors, in various cancer cell lines.ConclusionsTogether, these findings suggest that TMPRSS4 promotes CSC features in prostate cancer through upregulation of the SLUG- and TWIST1-induced stem cell factor SOX2 beyond EMT. Thus, TMPRSS4/SLUG-TWIST1/SOX2 axis may represent a novel mechanism involved in the control of tumor progression.

Project description:Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. The high mortality is directly associated with metastatic disease, which is thought to be initiated by colon cancer stem cells, according to the cancer stem cell (CSC) model. Consequently, early identification of those patients who are at high risk for metastasis is crucial for improved treatment and patient outcomes. Metastasis-associated in colon cancer 1 (MACC1) is a novel prognostic biomarker for tumor progression and metastasis formation independent of tumor stage. We previously showed an involvement of MACC1 in cancer stemness in the mouse intestine of our MACC1 transgenic mouse models. However, the expression of MACC1 in human CSCs and possible implications remain elusive. Here, we explored the molecular mechanisms by which MACC1 regulates stemness and the CSC-associated invasive phenotype based on patient-derived tumor organoids (PDOs), patient-derived xenografts (PDXs) and human CRC cell lines. We showed that CD44-enriched CSCs from PDO models express significantly higher levels of MACC1 and LGR5 and display higher tumorigenicity in immunocompromised mice. Similarly, RNA sequencing performed on PDO and PDX models demonstrated significantly increased MACC1 expression in ALDH1(+) CSCs, highlighting its involvement in cancer stemness. We further showed the correlation of MACC1 with the CSC markers CD44, NANOG and LGR5 in PDO models as well as established cell lines. Additionally, MACC1 increased stem cell gene expression, clonogenicity and sphere formation. Strikingly, we showed that MACC1 binds as a transcription factor to the LGR5 gene promoter, uncovering the long-known CSC marker LGR5 as a novel essential signaling mediator employed by MACC1 to induce CSC-like properties in human CRC patients. Our in vitro findings were further substantiated by a significant positive correlation of MACC1 with LGR5 in CRC cell lines as well as CRC patient tumors. Taken together, this study indicates that the metastasis inducer MACC1 acts as a cancer stem cell-associated marker. Interventional approaches targeting MACC1 would potentially improve further targeted therapies for colorectal cancer patients to eradicate CSCs and prevent cancer recurrence and distant metastasis formation.

Dataset Information

Sox2 is associated with cancer stem-like properties in colorectal cancer.

Publications

Sox2 is associated with cancer stem-like properties in colorectal cancer.

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