RET is a potential tumor suppressor gene in colorectal cancer

Luo, Yanxin; Tsuchiya, Karen D.; Park, D Il; Fausel, Rebecca; Kanngurn, Samornmas; Welcsh, Piri; Dzieciatkowski, Slavomir; Wang, J; Grady, William M.

doi:10.1038/onc.2012.225

Cited by 88 publications

(94 citation statements)

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“…In contrast to its well-established role as an oncogene for several cancer types, RET has been recently proposed to play tumor suppressor roles in colorectal cancer (CRC) and pituitary adenoma [46,47]. Such tumor suppressor role might be functionally linked to a pro-apoptotic role exerted by RET by behaving as a "dependence" receptor [48].…”

Section: Ret As a Tumor Suppressormentioning

confidence: 99%

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RET: A Multi-Faceted Gene in Human Cancer

2012

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Section: Ret As a Tumor Suppressormentioning

confidence: 99%

“…Moreover, in rare CRC samples, somatic mutations (V145G, R360W, and G593E) in RET extracellular domain impaired RET-mediated apoptosis of colon epithelial cells; thus, either RET downregulation or mutations causing loss of RET-mediated apoptosis may be selected during CRC formation [47].…”

Section: Ret As a Tumor Suppressormentioning

confidence: 99%

RET: A Multi-Faceted Gene in Human Cancer

2012

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“…It binds the ligands to form a multi-receptor complex that includes GFRα (GFRA) proteins to activate receptor tyrosine kinases in a variety of signaling. However, it has been found to be a tumor suppressor in colorectal cancer case and is methylated 55 . Moreover, the functional RET receptor complex includes RET and one of four glycosylphosphatidylinositol-anchored co-receptors, designated GDNF-α receptors, GFRα1, GFRα2, GFRα3 (GFRA3), and GFRα4 and Luo et al 55 observe that GFRA3 is expressed in the colorectal cancer cases.…”

Section: Dicationmentioning

confidence: 99%

“…However, it has been found to be a tumor suppressor in colorectal cancer case and is methylated 55 . Moreover, the functional RET receptor complex includes RET and one of four glycosylphosphatidylinositol-anchored co-receptors, designated GDNF-α receptors, GFRα1, GFRα2, GFRα3 (GFRA3), and GFRα4 and Luo et al 55 observe that GFRA3 is expressed in the colorectal cancer cases. GFRA3 was found to be downregulated on treatment with the ETC-1922159 and might have been highly expressed in the colorectal cancer case.…”

Section: Dicationmentioning

confidence: 99%

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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“…Genomic DNA was extracted and bisulfite converted, and methylation-specific PCR was conducted as previously described [32]. The primer sequences used are given as follows: RECQL methyl-specific forward primer, 5′-GCGGTCCCAAAAGGGTCAGTTCGGATA-TCGGATAGTTAAATATCG-3′; RECQL methyl-specific reverse primer, 5′-GCGGTCCCAAAAGGGTCAGTCCGATCAACAAA-CGAACGTA-3′; RECQL non-methyl-specific forward primer, 5′-GCGGTCCCAAAAGGGTCAGTTGGATATTGGATAGTTAA-ATATTGG-3′; RECQL non-methyl-specific reverse primer, 5′-GCG-GTCCCAAAAGGGTCAGTAAAAACCAATCAACAAACAAACA-TA-3′; RECQL5 methyl-specific forward primer, 5′-AATTAAAGGT-TGTTGGTTGGTTTC-3′; RECQL5 methyl-specific reverse primer, 5′-ACTACGCGACGAATATAAAATTACG-3′; RECQL5 nonmethyl-specific forward primer, 5′-AATTAAAGGTTGTTGG-TTGGTTTT-3; RECQL5 non-methyl-specific reverse primer, 5′-CTACACAACAAATATAAAATTACATA-3′.…”

Section: Methylation-specific Pcrmentioning

confidence: 99%

Altered RecQ Helicase Expression in Sporadic Primary Colorectal Cancers

Lao

Carter

Dzieciatkowski

et al. 2013

Journal of Surgical Research

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Deregulation of DNA repair enzymes occurs in cancers and may create a susceptibility to chemotherapy. Expression levels of DNA repair enzymes have been shown to predict the responsiveness of cancers to certain chemotherapeutic agents. The RECQ helicases repair damaged DNA including damage caused by topoisomerase I inhibitors, such as irinotecan. Altered expression levels of these enzymes in colorectal cancer (CRC) may influence the response of the cancers to irinotecan. Thus, we assessed RECQ helicase (WRN, BLM, RECQL, RECQL4, and RECQL5) expression in primary CRCs, matched normal colon, and CRC cell lines. We found that BLM and RECQL4 mRNA levels are significantly increased in CRC (P = .0011 and P < .0001, respectively), whereas RECQL and RECQL5 are significantly decreased (P = .0103 and P = .0029, respectively). RECQ helicase expression patterns varied between specific molecular subtypes of CRCs. The mRNA and protein expression of the majority of the RECQ helicases was closely correlated, suggesting that altered mRNA expression is the predominant mechanism for deregulated RECQ helicase expression. Immunohistochemistry localized the RECQ helicases to the nucleus. RECQ helicase expression is altered in CRC, suggesting that RECQ helicase expression has potential to identify CRCs that are susceptible to specific chemotherapeutic agents.

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RET is a potential tumor suppressor gene in colorectal cancer

Cited by 88 publications

References 50 publications

RET: A Multi-Faceted Gene in Human Cancer

RET: A Multi-Faceted Gene in Human Cancer

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

Altered RecQ Helicase Expression in Sporadic Primary Colorectal Cancers

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