SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells

Wuebben, Erin L.; Wilder, Phillip J.; Cox, Jesse L.; Grunkemeyer, James A.; Caffrey, Thomas C.; Hollingsworth, Michael A.; Rizzino, Angie

doi:10.18632/oncotarget.8994

Cited by 31 publications

(60 citation statements)

References 67 publications

(84 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SOX2 expression predicts poor survival of HCC patients and it promotes liver cancer cell invasion by activating Slug (24). In pancreatic ductal adenocarcinoma cells, SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug response (29). Moreover, Li et al demonstrated that SOX2 could promote tumor metastasis by stimulating epithelial-to-mesenchymal transition via regulation of Wnt/β-catenin signal pathway (30).…”

Section: Discussionmentioning

confidence: 99%

Loss of miR-638 promotes invasion and epithelial-mesenchymal transition by targeting SOX2 in hepatocellular carcinoma

2016

View full text Add to dashboard Cite

Aberrant expression of microRNAs has been identified as regulators of biological processes of hepatocellular carcinoma (HCC) by negatively regulating protein-coding mRNAs. Several studies have demonstrated that miR-638 expression was dysregulated in various human cancers. However, the clinical significance and underlying mechanisms of miR-638 involved in HCC remain to be elucidated. Herein, we confirmed that a reduced miR-638 expression was present in HCC tissues and cell lines. Our clinical analysis revealed that the downregulated miR-638 expression was significantly correlated with poor prognostic features including high Edmondson-Steiner grade, venous infiltration and advanced tumor-node-metastasis (TNM) stage. Moreover, we demonstrated that miR-638 was a novel independent prognostic marker for predicting 5-year survival of HCC patients. Functionally, overexpressed miR-638 expression inhibited cell migration and invasion, while downregulated miR-638 reversed the effect. In addition, miR-638 could regulate SOX2 by directly binding to its 3'-UTR. Alternation of SOX2 expression at least partially abolished the migration and invasion effects of miR-638 on HCC cells. Aberrant miR-638 expression could regulate the expression level of epithelial-to-mesenchymal transition markers in vitro and in vivo by modulating SOX2 expression. In conclusion, our data indicated that miR-638 functioned as a tumor suppressor gene and play a critical role in the development of HCC.

show abstract

Section: Discussionmentioning

confidence: 99%

Loss of miR-638 promotes invasion and epithelial-mesenchymal transition by targeting SOX2 in hepatocellular carcinoma

2016

View full text Add to dashboard Cite

show abstract

“…Several recent studies have shown that exogenous elevation of SOX2 can promote resistance to chemotherapeutics currently being used clinically [ 29 , 34 , 38 , 48 , 49 , 67 , 75 , 80 , 111 – 114 ]. In a report from Bareiss et al, ovarian cancer cell lines that did not express SOX2 and that were sensitive to carboplatin, cisplatin, and paclitaxel became resistant following stable, ectopic expression of SOX2 [ 80 ].…”

Section: Expression and Function Of Sox2 In Cancermentioning

confidence: 99%

“…Furthermore, it has been shown that inducible-overexpression and inducible-knockdown of SOX2 in PDAC cell lines altered responses to small molecule inhibitors targeting MEK and AKT signaling. In this study, overexpression of SOX2 protected PDAC cells from the growth inhibitory effects of MEK and AKT inhibitors; whereas, knocking down SOX2 enhanced the growth inhibition in the presence of these drugs [ 114 ]. While SOX2 may be acting to protect tumor cells through antiapoptotic signaling or quiescent-like phenotypes [ 29 , 37 , 67 , 75 ], SOX2 may also be promoting drug resistance through various ATP-binding cassette (ABC) transporters, including ABCG2, ABCC3, and ABCC6.…”

Section: Expression and Function Of Sox2 In Cancermentioning

confidence: 99%

“…Many studies have used stable overexpression and/or knockdown of SOX2 in tumor cell lines to better understand the roles of this transcription factor in cancer. Knockdown of SOX2 using either small interfering RNA (siRNA) or shRNA have been used in multiple studies [ 8 , 11 , 12 , 25 , 29 , 32 – 34 , 48 , 52 , 69 , 111 , 114 – 118 ]. Importantly, even partial reductions in SOX2 levels have been reported to significantly decrease cell viability, clonal growth, sphere formation, and tumorigenicity in multiple cancer types.…”

Section: Expression and Function Of Sox2 In Cancermentioning

confidence: 99%

See 1 more Smart Citation

The dark side of SOX2: cancer - a comprehensive overview

Wuebben

Rizzino²

2017

Oncotarget

Self Cite

178

161

View full text Add to dashboard Cite

The pluripotency-associated transcription factor SOX2 is essential during mammalian embryogenesis and later in life, but SOX2 expression can also be highly detrimental. Over the past 10 years, SOX2 has been shown to be expressed in at least 25 different cancers. This review provides a comprehensive overview of the roles of SOX2 in cancer and focuses on two broad topics. The first delves into the expression and function of SOX2 in cancer focusing on the connection between SOX2 levels and tumor grade as well as patient survival. As part of this discussion, we address the developing connection between SOX2 expression and tumor drug resistance. We also call attention to an under-appreciated property of SOX2, its levels in actively proliferating tumor cells appear to be optimized to maximize tumor growth - too little or too much SOX2 dramatically alters tumor growth. The second topic of this review focuses on the exquisite array of molecular mechanisms that control the expression and transcriptional activity of SOX2. In addition to its complex regulation at the transcriptional level, SOX2 expression and activity are controlled carefully by microRNAs, long non-coding RNAs, and post-translational modifications. In the Conclusion and Future Perspectives section, we point out that there are still important unanswered questions. Addressing these questions is expected to lead to new insights into the functions of SOX2 in cancer, which will help design novels strategies for more effectively treating some of the most deadly cancers.

show abstract

“…It was demonstrated that overexpression of SOX2 contributes to resistance of MCF-7 breast cancer cells to tamoxifen, whereas downregulation of SOX2 enhanced the sensitivity of MCF-7 cells to tamoxifen (17). In addition, it was found that knockdown of SOX2 in pancreatic ductal adenocarcinoma cells increased the response to small-molecule inhibitors targeting MEK and AKT signaling (18). A recent study indicated that down regulation of SOX2 reduced invasiveness and increased sensitivity to paclitaxel by preserving the epithelial-like properties of breast cancer stem cells (19).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of miR‑200c‑3p contributes to the resistance of breast cancer cells to paclitaxel by targeting SOX2

Chen

Tian

et al. 2018

Oncol Rep

View full text Add to dashboard Cite

Acquisition of resistance to paclitaxel is a major obstacle to successful treatment of breast cancer patients, but the molecular mechanisms underlying the development of drug resistance remain largely unclear. The aim of the present study was to investigate the role and mechanism of action of miR-200c-3p in the resistance of breast cancer to paclitaxel. It was observed that miR-200c-3p expression, as determined by reverse transcription-quantitative polymerase chain reaction analysis, was significantly downregulated in paclitaxel-resistant MCF-7/Tax cells compared with parental MCF-7 cells. Overexpression of miR-200c-3p increased the chemosensitivity to paclitaxel and enhanced apoptosis in MCF-7/Tax cells, whereas the downregulation of miR-200c-3p exerted the opposite effect. In addition, upregulation of miR-200c-3p in MCF-7/Tax cells suppressed the expression of sex-determining region Y-box 2 (SOX2) at the mRNA and protein levels. Dual-luciferase reporter assay demonstrated that SOX2 is a target of miR-200c-3p in MCF-7/Tax cells. Moreover, knockdown of SOX2 expression increased chemosensitivity to paclitaxel and upregulated miR-200c-3p expression in MCF-7/Tax cells. Taken together, the results of the present study indicated that miR-200c-3p plays a key role in the development of paclitaxel resistance in breast cancer, possibly partially through regulating SOX2 expression, suggesting that the miR-200c-3p-SOX2 loop may serve as a potential target for the reversal of paclitaxel resistance in breast cancer

show abstract

SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells

Cited by 31 publications

References 67 publications

Loss of miR-638 promotes invasion and epithelial-mesenchymal transition by targeting SOX2 in hepatocellular carcinoma

Loss of miR-638 promotes invasion and epithelial-mesenchymal transition by targeting SOX2 in hepatocellular carcinoma

The dark side of SOX2: cancer - a comprehensive overview

Downregulation of miR‑200c‑3p contributes to the resistance of breast cancer cells to paclitaxel by targeting SOX2

Contact Info

Product

Resources

About