Colorectal Cancer Biomarkers and the Potential Role of Cancer Stem Cells

Langan, Russell C.; Mullinax, John E.; Raiji, Manish T.; Upham, Trevor; Summers, Thomas A.; Stojadinovic, Alexander; Avital, Itzhak

doi:10.7150/jca.5832

Cited by 69 publications

(49 citation statements)

References 80 publications

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“…However, the markers that are currently known remain controversial for colon CSCs. Currently, CSCs are defined by expression of CD133, EpCAM, CD44, CD166, and Lgr5 [8,34,35]. Here, we demonstrated that CD133 and EpCAM are makers for EMT change of colon CSCs.…”

Section: Discussionmentioning

confidence: 72%

BMP-2 induces motility and invasiveness by promoting colon cancer stemness through STAT3 activation

Kim

Lee

et al. 2015

Tumor Biol.

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Bone morphogenetic proteins (BMPs) have been involved in metastatic progression and tumorigenesis of many cancer types. However, it remains unclear how BMP-2 contributes to the initiation and development of these cancers. Here, we investigated the role of BMP-2 in colon cancer stem cell (CSC) development from colon cancer cells. We also determined the effects of BMP-2 on CSC development and epithelial-mesenchymal transition (EMT) in human colon cancer cell lines HCT-116 and SW620. We found that BMP-2 enhanced sphere formation of colon cancer cells without serum. Also, BMP-2-induced spheres displayed up-regulation of stemness markers (CD133+ and EpCAM+) and increased drug resistance, hallmarks of CSCs. Importantly, expression of EMT activators p-Smad1/5 and Snail and N-cadherin was increased in the spheres' cells, indicating that BMP-2 signaling might result in CSC self-renewal and EMT. Furthermore, siRNA-mediated knockdown of signal transducer and activator of transcription 3 (STAT3) in HCT-116 cells reversed BMP-2-induced EMT and stem cell formation. Taken together, our results suggest that the BMP-2 induced STAT3-mediated induction of colon cancer cell metastasis requires an EMT and/or changes in CSC markers.

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Section: Discussionmentioning

confidence: 72%

BMP-2 induces motility and invasiveness by promoting colon cancer stemness through STAT3 activation

Kim

Lee

et al. 2015

Tumor Biol.

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“…FIR total knockout, FIR −/− , mouse is embryonic lethal before E9.5, suggesting that FIR is essential for embryogenesis. Proteins expressed during embryogenesis disappear during development but are re-expressed in cancers [27, 28], suggesting that FIR is crucial for carcinogenesis as well.…”

Section: Resultsmentioning

confidence: 99%

Haploinsufficiency of thec-myctranscriptional repressorFIR, as a dominant negative-alternative splicing model, promoted p53-dependent T-cell acute lymphoblastic leukemia progression by activating Notch1

et al. 2014

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FUSE-binding protein (FBP)-interacting repressor (FIR) is a c-myc transcriptional suppressor. A splice variant of FIR that lacks exon 2 in the transcriptional repressor domain (FIRΔexon2) upregulates c-myc transcription by inactivating wild-type FIR. The ratio of FIRΔexon2/FIR mRNA was increased in human colorectal cancer and hepatocellular carcinoma tissues. Because FIRΔexon2 is considered to be a dominant negative regulator of FIR, FIR heterozygous knockout (FIR+/−) C57BL6 mice were generated. FIR complete knockout (FIR−/−) was embryonic lethal before E9.5; therefore, it is essential for embryogenesis. This strongly suggests that insufficiency of FIR is crucial for carcinogenesis. FIR+/− mice exhibited prominent c-myc mRNA upregulation, particularly in the peripheral blood (PB), without any significant pathogenic phenotype. Furthermore, elevated FIRΔexon2/FIR mRNA expression was detected in human leukemia samples and cell lines. Because the single knockout of TP53 generates thymic lymphoma, FIR+/−TP53−/− generated T-cell type acute lymphocytic/lymphoblastic leukemia (T-ALL) with increased organ or bone marrow invasion with poor prognosis. RNA-sequencing analysis of sorted thymic lymphoma cells revealed that the Notch signaling pathway was activated significantly in FIR+/−TP53−/− compared with that in FIR+/+TP53−/− mice. Notch1 mRNA expression in sorted thymic lymphoma cells was confirmed using qRT-PCR. In addition, flow cytometry revealed that c-myc mRNA was negatively correlated with FIR but positively correlated with Notch1 in sorted T-ALL/thymic lymphoma cells. Moreover, the knockdown of TP53 or c-myc using siRNA decreased Notch1 expression in cancer cells. In addition, an adenovirus vector encoding FIRΔexon2 cDNA increased bleomycin-induced DNA damage. Taken together, these data suggest that the altered expression of FIRΔexon2 increased Notch1 at least partially by activating c-Myc via a TP53-independent pathway. In conclusion, the alternative splicing of FIR, which generates FIRΔexon2, may contribute to both colorectal carcinogenesis and leukemogenesis.

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“…[38][39][40][41] Although previous reports have focused on the possible relationship between CD44v and ovarian cancer survival, there is no unified view in this issue. 25,30,42,43 In regard to these unanswered questions, we used Kaplan-Meier analysis to evaluate the capacity of CD44 variant 6 expression to predict outcome in patients with ovarian cancer.…”

Section: Discussionmentioning

confidence: 97%

CD44 Variant 6 as a Predictive Biomarker for Distant Metastasis in Patients With Epithelial Ovarian Cancer

Motohara

Fujimoto

Tayama

et al. 2016

Obstetrics &Amp; Gynecology

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Colorectal Cancer Biomarkers and the Potential Role of Cancer Stem Cells

Cited by 69 publications

References 80 publications

BMP-2 induces motility and invasiveness by promoting colon cancer stemness through STAT3 activation

BMP-2 induces motility and invasiveness by promoting colon cancer stemness through STAT3 activation

Haploinsufficiency of thec-myctranscriptional repressorFIR, as a dominant negative-alternative splicing model, promoted p53-dependent T-cell acute lymphoblastic leukemia progression by activating Notch1

CD44 Variant 6 as a Predictive Biomarker for Distant Metastasis in Patients With Epithelial Ovarian Cancer

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