Clinicopathological significance and impact on outcomes of the gene expression levels of IGF-1, IGF-2 and IGF-1R, IGFBP-3 in patients with colorectal cancer: Overexpression of the IGFBP-3 gene is an effective predictor of outcomes in patients with colorectal cancer

Yamamoto, Naoto; Oshima, Takashi; Yoshihara, Kazuo; Aoyama, Toru; Hayashi, Tsutomu; Yamada, Takanobu; Sato, Tsutomu; Shiozawa, Manabu; Yoshikawa, Takaki; Morinaga, Soichiro; Rino, Yasushi; Kunisaki, Chikara; Tanaka, Katsuaki; Amaki, Makoto; Imada, Toshio; Masuda, Munetaka

doi:10.3892/ol.2017.5936

Cited by 20 publications

(17 citation statements)

References 36 publications

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“…Our analyses using the public database also indicated that an increased IGF1 mRNA was identified in patients with colon cancer as well as a shorter survival time, as compared to patients with a lower IGF1 mRNA level; HT29 colon cancer cells resistant to methotrexate expressed a significantly higher level of IGF1 mRNA as compared to their sensitive counterparts. A recent study corroborates with our view that IGF-signaling promotes the epithelial-to-mesenchymal transition (EMT) and stemness in colon cancer [ 32 ].…”

Section: Discussionsupporting

confidence: 86%

Destruxin B Suppresses Drug-Resistant Colon Tumorigenesis and Stemness Is Associated with the Upregulation of miR-214 and Downregulation of mTOR/β-Catenin Pathway

Huang

Tzeng

et al. 2018

Cancers

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Background: Drug resistance represents a major challenge for treating patients with colon cancer. Accumulating evidence suggests that Insulin-like growth factor (IGF)-associated signaling promotes colon tumorigenesis and cancer stemness. Therefore, the identification of agents, which can disrupt cancer stemness signaling, may provide improved therapeutic efficacy. Methods: Mimicking the tumor microenvironment, we treated colon cancer cells with exogenous IGF1. The increased stemness of IGF1-cultured cells was determined by ALDH1 activity, side-population, tumor sphere formation assays. Destruxin B (DB) was evaluated for its anti-tumorigenic and stemness properties using cellular viability, colony-formation tests. The mimic and inhibitor of miR-214 were used to treat colon cancer cells to show its functional association to DB treatment. In vivo mouse models were used to evaluate DB’s ability to suppress colon tumor-initiating ability and growth inhibitory function. Results: IGF1-cultured colon cancer cells showed a significant increase in 5-FU resistance and enhanced stemness properties, including an increased percentage of ALDH1+, side-population cells, tumor sphere generation in vitro, and increased tumor initiation in vivo. In support, using public databases showed that increased IGF1 expression was significantly associated with a poorer prognosis in patients with colon cancer. DB, a hexadepsipeptide mycotoxin, was able to suppress colon tumorigenic phenotypes, including colony and sphere formation. The sequential treatment of DB, followed by 5-FU, synergistically inhibited the viability of colon cancer cells. In vivo studies showed that DB suppressed the tumorigenesis by 5-FU resistant colon cells, and in a greater degree when combined with 5-FU. Mechanistically, DB treatment was associated with decreased the mammalian target of rapamycin (mTOR) and β-catenin expression and an increased miR-214 level. Conclusion: We provided evidence of DB as a potential therapeutic agent for overcoming 5-FU resistance induced by IGF1, and suppressing cancer stem-like properties in association with miR-214 regulation. Further investigation is warranted for its translation to clinical application.

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Section: Discussionsupporting

confidence: 86%

Destruxin B Suppresses Drug-Resistant Colon Tumorigenesis and Stemness Is Associated with the Upregulation of miR-214 and Downregulation of mTOR/β-Catenin Pathway

Huang

Tzeng

et al. 2018

Cancers

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“…CYR61 expression was associated with poor prognosis in patients with colorectal cancer [26] and it promotes cancer cells proliferation, invasion, survival, and metastasis [27, 28]. In addition to CYR61 , IGFBP3 [29] and GDF15 [30] are also effective predictors of outcomes in patients with colorectal cancer. WNT16B [31], NT5E [32], GPF15 [33], and CDC14A [34] are implicated in tumorigenesis via regulating tumor growth and EMT process.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: Ras-ERK1/2 signaling contributes to the development of colorectal cancer via regulating H3K9ac

et al. 2018

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Backgrounds/aimsRas is a control switch of ERK1/2 pathway, and hyperactivation of Ras-ERK1/2 signaling appears frequently in human cancers. However, the molecular regulation following by Ras-ERK1/2 activation is still unclear. This work aimed to reveal whether Ras-ERK1/2 promoted the development of colorectal cancer via regulating H3K9ac.MethodsA vector for expression of K-Ras mutated at G12 V and T35S was transfected into SW48 cells, and the acetylation of H3K9 was measured by Western blot analysis. MTT assay, colony formation assay, transwell assay, chromatin immunoprecipitation and RT-qPCR were performed to detect whether H3K9ac was contributed to K-Ras-mediated cell growth and migration. Furthermore, whether HDAC2 and PCAF involved in modification of H3K9ac following Ras-ERK1/2 activation were studied.ResultsK-Ras mutated at G12 V and T35S induced a significant activation of ERK1/2 signaling and a significant down-regulation of H3K9ac. Recovering H3K9 acetylation by using a mimicked H3K9ac expression vector attenuated the promoting effects of Ras-ERK1/2 on tumor cells growth and migration. Besides, H3K9ac can be deacetylated by HDAC2 and MDM2-depedent degradation of PCAF.ConclusionH3K9ac was a specific target for Ras-ERK1/2 signaling pathway. H3K9 acetylation can be modulated by HDAC2 and MDM2-depedent degradation of PCAF. The revealed regulation provides a better understanding of Ras-ERK1/2 signaling in tumorigenesis.

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“…No quantitative differences have been detected in mRNA expression of the two promoter types (class I and II transcripts), suggesting that genomic expression of IGF1 remains under a control of both P1 and P2 promoters in CRC and in normal colon. The quantitative analysis showed significantly lower expression of the total IGF1 mRNA, similarly to the results described by other authors [ 175 ]. Expression of all IGF1 transcripts in CRC was also lower compared to control samples [ 105 ].…”

Section: Igf1 Gene Alternative Splicing and Carcinogenesissupporting

confidence: 90%

“…Potential correlation between the levels of circulating IGF1 and CRC risk were reported in recent literature [ 174 ]. Similarly, lowered IGF1 protein expression was noted in cancer tissue compared with normal mucosa [ 175 ].…”

Section: Igf1 Gene Alternative Splicing and Carcinogenesismentioning

confidence: 99%

Role of Alternatively Spliced Messenger RNA (mRNA) Isoforms of the Insulin-Like Growth Factor 1 (IGF1) in Selected Human Tumors

Kasprzak

Szaflarski

2020

IJMS

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Insulin-like growth factor 1 (IGF1) is a key regulator of tissue growth and development that is also implicated in the initiation and progression of various cancers. The human IGF1 gene contains six exons and five long introns, the transcription of which is controlled by two promoters (P1 and P2). Alternate promoter usage, as well as alternative splicing (AS) of IGF1, results in the expression of six various variants (isoforms) of mRNA, i.e., IA, IB, IC, IIA, IIB, and IIC. A mature 70-kDa IGF1 protein is coded only by exons 3 and 4, while exons 5 and 6 are alternatively spliced code for the three C-terminal E peptides: Ea (exon 6), Eb (exon 5), and Ec (fragments of exons 5 and 6). The most abundant of those transcripts is IGF1Ea, followed by IGF1Eb and IGF1Ec (also known as mechano-growth factor, MGF). The presence of different IGF1 transcripts suggests tissue-specific auto- and/or paracrine action, as well as separate regulation of both of these gene promoters. In physiology, the role of different IGF1 mRNA isoforms and pro-peptides is best recognized in skeletal muscle tissue. Their functions include the development and regeneration of muscles, as well as maintenance of proper muscle mass. In turn, in nervous tissue, a neuroprotective function of short peptides, produced as a result of IGF1 expression and characterized by significant blood-brain barrier penetrance, has been described and could be a potential therapeutic target. When it comes to the regulation of carcinogenesis, the potential biological role of different var iants of IGF1 mRNAs and pro-peptides is also intensively studied. This review highlights the role of IGF1 isoform expression (mRNAs, proteins) in physiology and different types of human tumors (e.g., breast cancer, cervical cancer, colorectal cancer, osteosarcoma, prostate and thyroid cancers), as well as mechanisms of IGF1 spliced variants involvement in tumor biology.

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Clinicopathological significance and impact on outcomes of the gene expression levels of IGF-1, IGF-2 and IGF-1R, IGFBP-3 in patients with colorectal cancer: Overexpression of the IGFBP-3 gene is an effective predictor of outcomes in patients with colorectal cancer

Abstract: Abstract. The insulin-like growth factors (IGF) system is involved in tumor proliferation, invasion and metastasis in cancer. The current study investigated the association of IGF-1,

Cited by 20 publications

References 36 publications

Destruxin B Suppresses Drug-Resistant Colon Tumorigenesis and Stemness Is Associated with the Upregulation of miR-214 and Downregulation of mTOR/β-Catenin Pathway

Destruxin B Suppresses Drug-Resistant Colon Tumorigenesis and Stemness Is Associated with the Upregulation of miR-214 and Downregulation of mTOR/β-Catenin Pathway

RETRACTED ARTICLE: Ras-ERK1/2 signaling contributes to the development of colorectal cancer via regulating H3K9ac

Role of Alternatively Spliced Messenger RNA (mRNA) Isoforms of the Insulin-Like Growth Factor 1 (IGF1) in Selected Human Tumors

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