SALL4 as an Epithelial-Mesenchymal Transition and Drug Resistance Inducer through the Regulation of c-Myc in Endometrial Cancer

Liu, Lei; Zhang, Jing; Yang, Xiaoming; Feng, Cheng; Xu, Huali; Xi, Xiaowei

doi:10.1371/journal.pone.0138515

Cited by 63 publications

(80 citation statements)

References 41 publications

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“…It has been shown that using the dual PI3K/mTOR inhibitor NVP-BEZ235 inhibits the expression of c-MYC in pancreatic cancer cells (Sharma et al 2015). Moreover, c-MYC has also been linked to promoting EMT induction in endometrial cancer cells (Liu, et al 2015). Therefore, the decrease in c-MYC protein expression in the IRKD tumors in both the Rag/WT and Rag/MKR mice may contribute to the significantly decreased tumor sizes and reversal of EMT in the tumors of those mice.…”

Section: Discussionmentioning

confidence: 99%

EMT reversal in human cancer cells after IR knockdown in hyperinsulinemic mice

Zelenko

Gallagher

Antoniou

et al. 2016

Endocrine-Related Cancer

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Type 2 Diabetes (T2D) is associated with increased cancer risk and cancer-related mortality. Data herein show that we generated an immunodeficient hyperinsulinemic mouse by crossing the Rag1−/− mice, which have no mature B or T lymphocytes, with the MKR mouse model of T2D to generate the Rag1−/− (Rag/WT) and Rag1−/−/MKR+/+ (Rag/MKR) mice. The female Rag/MKR mice are insulin resistant and have significantly higher non-fasting plasma insulin levels compared to the Rag/WT controls. Therefore, we used these Rag/MKR mice to investigate the role of endogenous hyperinsulinemia on human cancer progression. In this study we show that hyperinsulinemia in the Rag/MKR mice increases the expression of mesenchymal transcription factors, TWIST1 and ZEB1, and increases the expression of the angiogenesis marker, vascular endothelial growth factor A (VEGFA). We also show that silencing the insulin receptor (IR) in the human LCC6 cancer cells leads to decreased tumor growth and metastases, suppression of mesenchymal markers Vimentin, SLUG, TWIST1, and ZEB1, suppression of angiogenesis markers, VEGFA and VEGFD, and re-expression of the epithelial marker, E-cadherin. The data in this paper demonstrate that IR knockdown in primary tumors partially reverses the growth promoting effects of hyperinsulinemia as well as highlighting the importance of the insulin receptor signaling pathway in cancer progression, and more specifically in epithelial-mesenchymal transition.

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Section: Discussionmentioning

confidence: 99%

EMT reversal in human cancer cells after IR knockdown in hyperinsulinemic mice

Zelenko

Gallagher

Antoniou

et al. 2016

Endocrine-Related Cancer

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“…Analyses of its expression and epigenetic status have shown that SALL4 is de-regulated and aberrantly expressed in various cancers (Review in 64 ) such as leukemia 65 , germ cell tumors 6667 , hepatocellular carcinoma (HCC) 2468 , gastric cancer 20,69–73 , colorectal carcinoma 74–76 , esophageal squamous cell carcinoma 77,78 , breast cancer 79–81 , endometrial cancer 82,83 , lung cancer 84–86 and glioma 87 . Functionally, SALL4 is important for the survival 38,80,82,88–93 , drug resistance 82,94 and metastasis 69,82 of many of these cancer cells (Figure 4).…”

Section: Sall4 In Cancersmentioning

confidence: 99%

“…Finally, SALL4 can regulate the expression of cell surface molecules such as EpCAM 91,113 , epithelial-mesenchymal transition (EMT) related factors (e.g. SNAI1 113 , CXCR4, TWIST1 91 , E-Cadherin 69,83,142 , VIM, and ZEB1 143 ) in cancers (Figure 5). …”

Section: Molecular Dissection Of Sall4 Functions In Cellsmentioning

confidence: 99%

SALL4, the missing link between stem cells, development and cancer

Tatetsu

Kong

Gao

et al. 2016

Gene

109

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There is a growing body of evidence supporting that cancer cells share many similarities with embryonic stem cells (ESCs). For example, aggressive cancers and ESCs share a common gene expression signature that includes hundreds of genes. Since ESC genes are not present in most adult tissues, they could be ideal candidate targets for cancer-specific diagnosis and treatment. This is an exciting cancer-targeting model. The major hurdle to test this model is to identify the key factors/pathway(s) within ESCs that are responsible for the cancer phenotype. SALL4 is one of few genes that can establish this link. The first publication of SALL4 is on its mutation in a human inherited disorder with multiple developmental defects. Since then, over 300 papers have been published on various aspects of this gene in stem cells, development, and cancers. This review aims to summarize our current knowledge of SALL4, including a SALL4-based approach to classify and target cancers. Many questions about this important gene still remain unanswered, specifically, on how this gene regulates cell fates at a molecular level. Understanding SALL4’s molecular functions will allow development of specific targeted approaches in the future.

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“…In addition to hematopoietic malignancies, SALL4 is also found to be upregulated in solid tumours including liver cancer, 13, 14 colon cancer, 15, 16 breast cancer, 17, 18 endometrial cancer, 19, 20 lung cancer 21, 22 and glioma. 23 The recent studies also suggest an oncogenic role of SALL4 in solid tumours.…”

Section: Introductionmentioning

confidence: 99%

SALL4 promotes gastric cancer progression through activating CD44 expression

Yuan

Zhang

et al. 2016

Oncogenesis

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The stem cell factor SALL4 (Sal-like protein 4) plays important roles in the development and progression of cancer. SALL4 is critically involved in tumour growth, metastasis and therapy resistance. However, the underlying mechanisms responsible for the oncogenic roles of SALL4 have not been well characterized. In this study, we demonstrated that SALL4 knockdown by short hairpin RNA greatly inhibited the proliferation, migration and invasion of gastric cancer cells. We further confirmed the inhibitory effects of SALL4 knockdown on gastric cancer cells by using a tetracycline-inducible system. Mechanistically, SALL4 knockdown downregulated the expression of CD44. The results of luciferase assay and chromatin immunoprecipitation study showed that SALL4 bound to CD44 promoter region and transcriptionally activated CD44. The results of rescue study revealed that CD44 overexpression antagonized SALL4 knockdown-mediated inhibition of gastric cancer cell proliferation, migration, and invasion in vitro and gastric cancer growth in vivo. Collectively, our findings indicate that SALL4 promotes gastric cancer progression through directly activating CD44 expression, which suggests a novel mechanism for the oncogenic roles of SALL4 in gastric cancer and represents a new target for gastric cancer therapy.

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SALL4 as an Epithelial-Mesenchymal Transition and Drug Resistance Inducer through the Regulation of c-Myc in Endometrial Cancer

Cited by 63 publications

References 41 publications

EMT reversal in human cancer cells after IR knockdown in hyperinsulinemic mice

EMT reversal in human cancer cells after IR knockdown in hyperinsulinemic mice

SALL4, the missing link between stem cells, development and cancer

SALL4 promotes gastric cancer progression through activating CD44 expression

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