Downregulation of PRRX1 Confers Cancer Stem Cell-Like Properties and Predicts Poor Prognosis in Hepatocellular Carcinoma

Hirata, Hidenari; Sugimachi, Keizō; Takahashi, Yusuke; Ueda, Masami; Sakimura, Shotaro; Uchi, Ryutaro; Kurashige, Junji; Takano, Yuki; Nanbara, Sho; Komatsu, Hisateru; Saito, Tomoko; Shinden, Yoshiaki; Iguchi, Tomohiro; Eguchi, Hidetoshi; Atsumi, Kazuhiko; Sakamoto, Katsumi; Doi, Toshiro; Hirakawa, Masakazu; Honda, Hiroshi; Mimori, Koshi

doi:10.1245/s10434-014-4242-0

Cited by 27 publications

(34 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In agreement, FD-conditioned HCC (Mahlavu and SK-Hep1), glioblastoma multiforme (U87MG) and lung cancer (H441) cells showed a significant increase in self-renewal ability as evident by the increased number of spheres formed and expression level of stemness associated markers such as Oct4, β-catenin and the percentage of CD133-positive cells. A recent study demonstrated that downregulation of paired related homeobox 1 (PRRX1) is associated with the acquisition of cancer stem cell (CSC)-like properties and poor prognosis in HCC patients [38]. In agreement, we also found that PRRX1 was down-regulated in the HCC spheres generated under FD condition.…”

Section: Discussionsupporting

confidence: 86%

Folate deficient tumor microenvironment promotes epithelial-to-mesenchymal transition and cancer stem-like phenotypes

Huang²,

Huang

et al. 2016

Oncotarget

View full text Add to dashboard Cite

Clinically, serum level of folate has been negatively correlated to the stage and progression of liver cancer. Nevertheless, the functional consequence of folate deficiency (FD) in malignancy has not been fully investigated. Human hepatocellular carcinoma (HCC) cells (as study model) and other cancer types such as lung and glioma were cultured under folate deficient (FD) and folate complete (FD) conditions. Molecular characterization including intracellular ROS/RNS (reactive oxygen/nitrogen species), viability, colony formation, cancer stem-like cell (CSC) phenotype analyses were performed. In vivo tumorigenesis under FD and FC conditions were also examined. FD induced a significant increase in ROS and RNS, suppressing proliferative ability but inducing metastatic potential. Mesenchymal markers such as Snail, ZEB2, and Vimentin were significantly up-regulated while E-cadherin down-regulated. Importantly, CSC markers such as Oct4, β-catenin, CD133 were induced while PRRX1 decreased under FD condition. Furthermore, FD-conditioned HCC cells showed a decreased miR-22 level, leading to the increased expression of its target genes including HDAC4, ZEB2 and Oct4. Finally, xenograft mouse model demonstrated that FD diet promoted tumorigenesis and metastasis as compared to their FC counterparts. Our data provides rationales for the consideration of folate supplement as a metastasis preventive measure.

show abstract

Section: Discussionsupporting

confidence: 86%

Folate deficient tumor microenvironment promotes epithelial-to-mesenchymal transition and cancer stem-like phenotypes

Huang²,

Huang

et al. 2016

Oncotarget

View full text Add to dashboard Cite

show abstract

“…Paired-related homeobox 1 (PRRX1) was recently identified as a new EMT inducer (11). Furthermore, aberrant expression of PRRX1 is significantly associated with poor prognosis in various solid tumors including breast (11), colorectal (12), gastric cancer (13) and HCC (14). High PRRX1 expression levels were significantly associated with reduced metastasis and good prognosis in breast cancer (11), but the opposite relationship was observed in colorectal cancer and gastric cancer (12,13).…”

Section: Introductionmentioning

confidence: 99%

“…High PRRX1 expression levels were significantly associated with reduced metastasis and good prognosis in breast cancer (11), but the opposite relationship was observed in colorectal cancer and gastric cancer (12,13). Downregulation of PRRX1 expression contributed to the poor prognosis of patients with breast cancer and HCC through acquisition of CSC-like properties (11,14). However, the direct mechanisms through which PRRX1 regulates HCC cells is still unclear.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of PRRX1 via the p53-dependent signaling pathway predicts poor prognosis in hepatocellular carcinoma

et al. 2017

View full text Add to dashboard Cite

Paired-related homeobox 1 (PRRX1) has been identified as a novel molecule associated with induction of epithelial-mesenchymal transition (EMT), acquisition of cancer stem cell like properties and poor prognosis in tumors. However, the function of PRRX1 in hepatocellular carcinoma has not been elucidated. In the present study, we observed that PRRX1 expression levels were downregulated and positively correlated with the downregulated expression of p53 in hepatocellular carcinoma specimens. Decreased expression of PRRX1 and/or p53 by siRNA induced both the migration and the invasion features of HCC cells in vitro. Furthermore, the loss of PRRX1 inhibits hepatocellular carcinoma (HCC) cell apoptosis, an anti-apoptotic expression profile was upregulated accompanied by downregulated expression of p53. HCC patients with low-expression of both PRRX1 and p53 had a significantly shorter overall and disease-free survival. These findings demonstrate that PRRX1 plays an important role in metastasis and apoptosis of HCC cells through the p53-dependent signaling pathway and is expected to become a novel biomarker associated with patient prognosis and survival.

show abstract

“…CD13, which helps pause LCSCs in G1/G0 phase of the cell cycle [25], has already proven a useful drug target: the combination of a CD13 inhibitor with the genotoxin fluorouracil (5-FU) led to significantly smaller tumor size than either drug on its own in a mouse xenograft tumor model [26]. CD13 is special among LCSC markers because its level changes during differentiation of LCSCs in culture [36]: upregulation of CD13 is associated with the epithelial-mesenchymal transition and with a reduction in apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of microRNA-21 strengthens stem cell-like characteristics in a hepatocellular carcinoma cell line

et al. 2016

View full text Add to dashboard Cite

BackgroundLiver cancer stem cells (LCSCs) have been shown to express higher levels of microRNA-21 (miR-21). Here, we examine the possible contributions of miR-21 to the phenotype of LCSCs in culture and in xenograft tumors in nude mice.MethodsThe hepatocellular carcinoma cell line MHCC-97H was stably transformed with a retroviral vector to establish cells overexpressing miR-21, while a cell line transformed with empty vector served as a negative control. RT-PCR and Western blotting were used to evaluate the effects of miR-21 overexpression on the expression of various LCSC markers, a Transwell assay was used to assess the effects on cell migration and invasion, and a spheroid formation assay was used to examine the effects on clonogenesis. The effects of miR-21 overexpression were also examined in tumors in nude mice.ResultsAn MHCC-97H cell line was constructed that stably overexpresses miR-21 at 7.78 ± 1.51-fold higher levels than the negative control cell line. Expression of the LCSC markers CD13, Ep-CAM, CD90, and OCT4 was significantly higher in the miR-21-overexpressing cell line than in the negative control at both mRNA and protein levels. The overexpressing cell line formed larger, tighter, and more numerous spheroids. Overexpression of miR-21 was associated with greater cell migration and invasion. Tumors of overexpressing cells in nude mice had a significantly larger mean volume after 34 days of growth (773.62 ± 163.46 mm3) than tumors of negative control cells (502.79 ± 33.94 mm3, p = 0.048), as well as greater mean weight (0.422 ± 0.019 vs. 0.346 ± 0.006 g, p = 0.003).ConclusionsOverexpression of miR-21 strengthens the phenotype of LCSCs, facilitating invasion, migration, and tumorigenesis in hepatocellular carcinoma.

show abstract

Downregulation of PRRX1 Confers Cancer Stem Cell-Like Properties and Predicts Poor Prognosis in Hepatocellular Carcinoma

Abstract: Downregulation of PRRX1 expression contributes to the poor prognosis of patients with HCC through acquisition of CSC-like properties.

Cited by 27 publications

References 21 publications

Folate deficient tumor microenvironment promotes epithelial-to-mesenchymal transition and cancer stem-like phenotypes

Folate deficient tumor microenvironment promotes epithelial-to-mesenchymal transition and cancer stem-like phenotypes

Downregulation of PRRX1 via the p53-dependent signaling pathway predicts poor prognosis in hepatocellular carcinoma

Overexpression of microRNA-21 strengthens stem cell-like characteristics in a hepatocellular carcinoma cell line

Contact Info

Product

Resources

About