Significance of Polypyrimidine Tract–Binding Protein 1 Expression in Colorectal Cancer

Takahashi, Hidekazu; Nishimura, Junichi; Kagawa, Yutaka; Kano, Yoshihiro; Takahashi, Yusuke; Wu, Xin; Hiraki, Masayuki; Hamabe, Atsushi; Konno, Masamitsu; Haraguchi, Naotsugu; Takemasa, Ichiro; Mizushima, Tsunekazu; Ishii, Masaru; Mimori, Koshi; Ishii, Hideshi; Doki, Yuichiro; Mori, Masaki; Yamamoto, Hirofumi

doi:10.1158/1535-7163.mct-14-0142

Cited by 64 publications

(70 citation statements)

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“…This observation is consistent with the findings that hnRNPI is aberrantly expressed in colorectal cancer cells [24,31], and a number of hnRNPI targeting genes are abnormally spliced in colorectal cancer [24–30]. While it is possible that the colorectal cancer development in the hnRNPI-deficient mice may be a consequence of impaired neonatal host-microbe homeostasis, it is more likely that hnRNPI plays additional roles in preventing colitis and colorectal cancer development in adulthood.…”

Section: Discussionsupporting

confidence: 89%

“…hnRNPI, also known as polypyrimidine tract-binding protein (PTB), plays important roles in alternative splicing and other post-transcriptional regulatory events [22,23]. A number of hnRNPI targets are abnormally spliced in intestinal inflammatory and neoplastic diseases [24–31], suggesting that hnRNPI-dependent post-transcriptional control may play important roles in pathogenesis of these diseases. To determine hnRNPI functions in mammalian intestinal homeostasis and more importantly, to understand how malfunction of this protein contributes to inflammation and colorectal cancer, we have generated IEC-specific hnRNPI knockout mice.…”

Section: Introductionmentioning

confidence: 99%

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hnRNP I regulates neonatal immune adaptation and prevents colitis and colorectal cancer

et al. 2017

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The intestinal epithelium plays a critical role in host-microbe homeostasis by sensing gut microbes and subsequently initiating proper immune responses. During the neonatal stage, the intestinal epithelium is under immune repression, allowing the transition for newborns from a relatively sterile intra-uterine environment to one that is rich in foreign antigens. The mechanism underlying such immune repression remains largely unclear, but involves downregulation of IRAK1 (interleukin-1 receptor-associated kinase), an essential component of toll-like receptor-mediated NF-κB signaling. We report here that heterogeneous nuclear ribonucleoprotein I (hnRNPI), an RNA binding protein, is essential for regulating neonatal immune adaptation. We generated a mouse model in which hnRNPI is ablated specifically in the intestinal epithelial cells, and characterized intestinal defects in the knockout mice. We found that loss of hnRNPI function in mouse intestinal epithelial cells results in early onset of spontaneous colitis followed by development of invasive colorectal cancer. Strikingly, the epithelium-specific hnRNPI knockout neonates contain aberrantly high IRAK1 protein levels in the colons and fail to develop immune tolerance to environmental microbes. Our results demonstrate that hnRNPI plays a critical role in establishing neonatal immune adaptation and preventing colitis and colorectal cancer.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

hnRNP I regulates neonatal immune adaptation and prevents colitis and colorectal cancer

et al. 2017

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“…4). PTB expression levels are significantly up-regulated in breast, ovarian, glioblastoma, colorectal, and mucosal cancerous tissues compared with the corresponding normal tissues (Jin et al 2000;He et al 2004He et al , 2007He et al , 2014Takahashi et al 2015). PTB controls alternative splicing of target genes, such as pyruvate kinase PKM2 (Clower et al 2010), fibroblast growth factor receptor-1α-exon FGFR-1 (Jin et al 2000), and multidrug resistance protein 1 (MRP1), which contributes to the drug-resistance phenotype associated with many cancers (He et al 2004).…”

Section: Hnrnpk-heterogeneous Nuclear Ribonucleoprotein Kmentioning

confidence: 99%

Splicing-factor alterations in cancers

Anczuków

Krainer

2016

RNA

227

247

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Tumor-associated alterations in RNA splicing result either from mutations in splicing-regulatory elements or changes in components of the splicing machinery. This review summarizes our current understanding of the role of splicing-factor alterations in human cancers. We describe splicing-factor alterations detected in human tumors and the resulting changes in splicing, highlighting cell-type-specific similarities and differences. We review the mechanisms of splicing-factor regulation in normal and cancer cells. Finally, we summarize recent efforts to develop novel cancer therapies, based on targeting either the oncogenic splicing events or their upstream splicing regulators.

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“…Furthermore, high expression of PTBP1 has been demonstrated to be associated with aggressive behavior of several types of cancer, especially in glioma and ovarian tumors [16, 17]. A recent study showed that PTBP1 mRNA higher expressed in primary colorectal tumor samples than the normal colonic epithelium and indicated poor prognosis [20]. PTBP1 is the critical determinant of PKM embryonic pyruvate kinase isoform 2, which universally over-expressed in cancer for promoting aerobic glycolysis and may affect drug resistance, in transformed cells [21–25].…”

Section: Introductionmentioning

confidence: 99%

High expression of PTBP1 promote invasion of colorectal cancer by alternative splicing of cortactin

et al. 2017

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Polypyrimidine tract-binding protein 1 (PTBP1) involving in almost all steps of mRNA regulation including alternative splicing metabolism during tumorigenesis due to its RNA-binding activity. Initially, we found that high expressed PTBP1 and poor prognosis was interrelated in colorectal cancer (CRC) patients with stages II and III CRC, which widely different in prognosis and treatment, by immunohistochemistry. PTBP1 was also upregulated in colon cancer cell lines. In our study, knockdown of PTBP1 by siRNA transfection decreased cell proliferation and invasion in vitro. Denovirus shRNA knockdown of PTBP1 inhibited colorectal cancer growth in vivo. Furthermore, PTBP1 regulates alternative splicing of many target genes involving in tumorgenesis in colon cancer cells. We confirmed that the splicing of cortactin exon 11 which was only contained in cortactin isoform-a, as a PTBP1 target. Knockdown of PTBP1 decreased the expression of cortactin isoform-a by exclusion of exon 11. Also the mRNA levels of PTBP1 and cortactin isoform-a were cooperatively expressed in colorectal cancer tissues. Knocking down cortactin isoform-a significantly decreased cell migration and invasion in colorectal cancer cells. Overexpression of cortactin isoform-a could rescue PTBP1-knockdown effect of cell motility. In summary the study revealed that PTBP1 facilitates colorectal cancer migration and invasion activities by inclusion of cortactin exon 11.

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Significance of Polypyrimidine Tract–Binding Protein 1 Expression in Colorectal Cancer

Cited by 64 publications

References 50 publications

hnRNP I regulates neonatal immune adaptation and prevents colitis and colorectal cancer

hnRNP I regulates neonatal immune adaptation and prevents colitis and colorectal cancer

Splicing-factor alterations in cancers

High expression of PTBP1 promote invasion of colorectal cancer by alternative splicing of cortactin

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