Ascl2 Knockdown Results in Tumor Growth Arrest by miRNA-302b-Related Inhibition of Colon Cancer Progenitor Cells

Zhu, Rong; Yang, Yongtao; Yin, Tian; Bai, Jianying; Zhang, Xin; Li, Xiaohuan; Peng, Zhihong; He, Yonghong; Chen, Lei; Pan, Qiong; Fang, Dian‐Chun; Chen, Wensheng; Chen, Qian; Bian, Xiu‐Wu; Wang, Rongquan

doi:10.1371/journal.pone.0032170

Cited by 71 publications

(91 citation statements)

References 36 publications

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“…All 7 downregulated genes are reported canonical Wnt signaling target genes (36,37). Several of these genes, ASCL2, LGR5, and TDGF1, have also been directly associated with CSCs in various tumor types, supporting a role for the RSPO pathway in CSC biology and consistent with the in vivo tumorigenicity results presented herein (38)(39)(40). Downregulation of Wnt and stem cell genes by anti-RSPO treatment could be involved in the sensitization of tumor cells to chemotherapeutic agents (41,42).…”

Section: Rspo Blockade Inhibits Stem Cell Signaling Pathways In Tumorssupporting

confidence: 74%

Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types

et al. 2016

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Deregulation of the b-catenin signaling has long been associated with cancer. Intracellular components of this pathway, including axin, APC, and b-catenin, are frequently mutated in a range of human tumors, but the contribution of specific extracellular ligands that promote cancer development through this signaling axis remains unclear. We conducted a reporter-based screen in a panel of human tumors to identify secreted factors that stimulate b-catenin signaling. Through this screen and further molecular characterization, we found that R-spondin (RSPO) proteins collaborate with Wnt proteins to activate b-catenin. RSPO family members were expressed in several human tumors representing multiple malignancies, including ovarian, pancreatic, colon, breast, and lung cancer. We generated specific monoclonal antibody antagonists of RSPO family members and found that anti-RSPO treatment markedly inhibited tumor growth in human patient-derived tumor xenograft models, either as single agents or in combination with chemotherapy. Furthermore, blocking RSPO signaling reduced the tumorigenicity of cancer cells based on serial transplantation studies. Moreover, geneexpression analyses revealed that anti-RSPO treatment in responsive tumors strongly inhibited b-catenin target genes known to be associated with cancer and normal stem cells. Collectively, our results suggest that the RSPO family is an important stimulator of b-catenin activity in many human tumors and highlight a new effective approach for therapeutically modulating this fundamental signaling axis. Cancer Res; 76(3); 713-23. Ó2015 AACR.

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Section: Rspo Blockade Inhibits Stem Cell Signaling Pathways In Tumorssupporting

confidence: 74%

Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types

et al. 2016

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“…Several studies have exhibited the influence of miRNAs in colon cancer tumorigenesis, including miR-145 [13], let-7 [14], miR-320b [15]. These observations focus attention on miRNA based treatment for colon cancer [16,17].…”

Section: Discussionmentioning

confidence: 99%

MiR-495-3p facilitates colon cancer cell proliferation via Wnt/β-catenin signaling pathway by restraining Wnt inhibitory factor

Lin¹,

Tong²,

Li³

et al. 2017

Trop. J. Pharm Res

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Purpose: To demonstrate whether miR-495-3p promote the occurrence of colon cancer and development of colon cancer stem cells by inhibiting Wnt inhibitory factor (WIF1). Methods: The level of MiRNA and mRNA in cells were tested by real-time polymerase chain reaction (RT-PCR). Cell viability was assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Cell spheroid formation was measured by colony assay. Expression protein was

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“…In a more recent work, ASCL2 has been found to play a major role in stemness in colon crypts and is implicated in colon cancer 30 . Switching off the ASCL2 leads to a literal blockage of the stemness process and vice versa.…”

Section: Wnt10bmentioning

confidence: 95%

Revealing ETC-1922159 Affected Unknown 3<em><sup>rd</sup></em> order WNT10B-X-X Combinations, in Silico

Sinha¹

2017

Preprint

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WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. WNTs have been found to directly affect the stemness of the tumor cells via regulation of ASCL2. Switching off the ASCL2 literally blocks the stemness process of the tumor cells and vice versa. Furthermore, recent findings suggest BVES to be highly suppressed in malignancies and in vitro deletions of BVES show higher Wnt signaling activity to induce stemness. WNT10B was found to be highly expressed in such cases. Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be affecting the pathway under certain conditions. For example, WNT10B-ASCL2 is one such 2 nd order combination whose relation needs to be tested under the influence of recently developed porcupine-WNT inhibitor ETC-1922159. The inhibitor is known to suppress PORCN (porcupine) and thus inhibit a range of oncogenes known to be directly or indirectly affected by the Wnts. In a recent unpublished work in bioRxiv, Sinha 1 , we had the opportunity to rank these unknown biological hypotheses for down regulated genes at 2 nd order level after the drug was administered. The in silico observations showed that the combination of WNT10B-ASCL2 was assigned a relatively lower rank, thus validating the pipeline's efficacy with the confirmed wet lab experiment that indicate that both WNT10B and ASCL2 were down regulated after treatment in cancer cells. Here, we take one step further by in silico analysis of the 3 rd order combinations of WNT10B-X-X (X can be known or unknown factor), from a range of 100 randomly picked down regulated genes after ETC-1922159 treatment. The pipeline uses the density based HSIC (Hilbert Schmidt Information Criterion) sensitivity index with an rbf (radial basis function) kernel, which is known to be highly effective in sensitivity analysis. Various unknown/unexplored/untested 3 rd order biological hypotheses emerge some of which are confirmed in wet lab, while others need to be tested. The potential of such ranking is indispensable in the current era of search in a vast combinatorial forest. KEYWORDS -WNT pathway; porcupine inhibitor ETC-1922159; sensitivity analysis; colorectal cancer; unknown biological hypotheses; combinatorial search space; support vector ranking Conference, from 6-11 August 2017, held Significance WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. Often, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be involved in the pathway. The current work reveals at in silico level, the 3rd order WNT10B associated combinations that might be affected by the admin...

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Ascl2 Knockdown Results in Tumor Growth Arrest by miRNA-302b-Related Inhibition of Colon Cancer Progenitor Cells

Cited by 71 publications

References 36 publications

Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types

Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types

MiR-495-3p facilitates colon cancer cell proliferation via Wnt/β-catenin signaling pathway by restraining Wnt inhibitory factor

Revealing ETC-1922159 Affected Unknown 3<em><sup>rd</sup></em> order WNT10B-X-X Combinations, in Silico

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