Paired Related Homeobox 1 Research Articles

First case report of a NUP98-PMX1 rearrangement in de novo acute myeloid leukemia and literature review

BackgroundThe nucleoporin 98 (NUP98)-paired related homeobox 1 (PMX1) fusion gene, which results from t(1;11)(q23;p15), is rare in patients with acute myeloid leukemia (AML). Currently, only two cases of chronic myeloid leukemia in the accelerated phase or blast crisis and three cases of therapy-related AML have been reported. Here, we first report a patient with de novo AML carrying the NUP98-PMX1 fusion gene.Case presentationA 49-year-old man diagnosed with AML presented the karyotype 46,XY,t(1;11)(q23;p15)[20] in bone marrow (BM) cells. Fluorescence in situ hybridization analysis using dual-color break-apart probes showed the typical signal pattern. Reverse transcription-polymerase chain reaction (RT-PCR) analysis suggested the presence of the NUP98-PMX1 fusion transcript. The patient received idarubicin and cytarabine as induction chemotherapy. After 3 weeks, the BM aspirate showed complete remission, and the RT-PCR result for the NUP98-PMX1 fusion gene was negative. Subsequently, the patient received three cycles of high-dose Ara-c as consolidation chemotherapy, after which he underwent partially matched (human leukocyte antigen–DP locus mismatch) unrelated allogeneic hematopoietic stem cell transplantation (HSCT). The follow-up period ended on September 30, 2020 (6 months after HSCT), and the patient exhibited no recurrence or transplantation-related complications.ConclusionThis is the first report of a patient with de novo AML carrying the NUP98-PMX1 fusion gene. The reported case may contribute to a more comprehensive profile of the NUP98-PMX1 rearrangement, but mechanistic studies are warranted to fully understand the role of this fusion gene in leukemia pathogenesis.

Activation of COL11A1 by PRRX1 promotes tumor progression and radioresistance in ovarian cancer

Purpose Although radiotherapy is a common treatment option for all kinds of cancer patients, including ovarian cancer, a major obstacle limiting its application in the development of resistance. Therefore, it is urgently needed to clarify the mechanism of radiosensitivity modulation. Materials and methods We obtained open datasets and analyzed the expression of collagen type XI alpha 1 (COL11A1) in ovarian cancer patients with different stages. Meanwhile, the correlation of COL11A1 and survival outcomes is determined by Kaplan–Meier analysis. The role of COL11A1 in cell proliferation was observed in an in vitro knockdown system. SKOV3 radioresistant cells were established to determine the role of COL11A1 on radioresistant in ovarian cancer. Results and discussion COL11A1 were highly enriched in late-stage ovarian cancer tumor tissues and negatively correlated with survival outcomes in ovarian cancer. The functional analysis found that COL11A1 promoted ovarian cancer cell proliferation in vitro. Importantly, COL11A1 decreased radiosensitivity in ovarian cancer by AKT activation. Paired related homeobox 1 (PRRX1) acted as an upstream transcription factor to regulate COL11A1 expression in ovarian cancer. Increased COL11A1 expression is related to low survival outcomes and radiosensitivity in ovarian cancer. Conclusions Targeting COL11A1 is a promising strategy for improving radiotherapy efficiency.

Isolation of PRRX1-positive adult pituitary stem/progenitor cells from the marginal cell layer of the mouse anterior lobe.

We recently suggested that paired-related homeobox 1 (PRRX1) and sex-determining region Y-box 2 (SOX2) double-positive (PRRX1/SOX2-positive) cells are pituitary stem/progenitor cells. The present study aimed to isolate PRRX1-positive cells located in the pituitary stem/progenitor cell niche. Immunohistochemical analysis revealed that PRRX1/SOX2-positive cells were located mainly in the marginal cell layer (MCL)-niche of the adult mouse pituitary gland, but were rarely present in the parenchymal-niche. Two-dimensional cultivation of primary cells from the anterior lobe (AL), including the MCL-niche, achieved efficient proliferation of PRRX1/SOX2-positive cells with high expression levels of pituitary stem/progenitor cell and niche markers. In contrast, primary cells from the AL, excluding the MCL-niche, showed limited growth. When isolated PRRX1/SOX2-positive cells and clusters of the parenchymal-niche were compared immunocytochemically, aquaporin 5, a marker of the MCL-niche, was detected only in isolated cells. Three-dimensional cultivation of isolated PRRX1/SOX2-positive cells promoted the formation of cystic-like spheroids and differentiation into endocrine cells. Thus, PRRX1-positive adult pituitary stem/progenitor cells were successfully isolated from the MCL-niche. The present study provides a powerful tool to analyze the cell supply system in the pituitary gland.

PRRX1 promotes malignant properties in human osteosarcoma

Paired related homeobox 1 (PRRX1) is a marker of limb bud mesenchymal cells, and deficiency of p53 or Rb in Prrx1-positive cells induces osteosarcoma in several mouse models. However, the regulatory roles of PRRX1 in human osteosarcoma have not been defined. In this study, we performed PRRX1 immunostaining on 35 human osteosarcoma specimens to assess the correlation between PRRX1 level and overall survival. In patients with osteosarcoma, the expression level of PRRX1 positively correlated with poor prognosis or the ratio of lung metastasis. Additionally, we found PRRX1 expression on in 143B cells, a human osteosarcoma line with a high metastatic capacity. Downregulation of PRRX1 not only suppressed proliferation and invasion but also increased the sensitivity to cisplatin and doxorubicin. When 143B cells were subcutaneously transplanted into nude mice, PRRX1 knockdown decreased tumor sizes and rates of lung metastasis. Interestingly, forskolin, a chemical compound identified by Connectivity Map analysis using RNA expression signatures during PRRX1 knockdown, decreased tumor proliferation and cell migration to the same degree as PRRX1 knockdown. These results demonstrate that PRRX1 promotes tumor malignancy in human osteosarcoma.

Paired‑related homeobox1 overexpression promotes multidrug resistance via PTEN/PI3K/AKT signaling in MCF‑7 breast cancer cells.

Multidrug resistance (MDR) is a major cause of disease relapse and mortality in breast cancer. Paired-related homeobox 1 (PRRX1) is associated with the epithelial-mesenchymal transition (EMT), which is involved in tumor development, including cell invasion and MDR. However, the effect of PRRX1 on MDR had not clearly established. The present study investigated the influence of PRRX1 on MDR and the underlying molecular mechanisms in MCF-7 breast cancer cells. MCF-7 cells were divided into PRRX1+ group (cells transfected with a recombinant plasmid carrying the PRRX1 gene), negative control group (cells transfected with a blank vector) and blank group (untreated cells). It was found that the relative protein and mRNA expression levels of PRRX1, N-cadherin, vimentin and P-glycoprotein were significantly higher in PRRX1-overexpressing MCF-7 cells compared with those in control cells. The half-maximal inhibitory concentration of three groups after treatment with docetaxel and cis-platinum complexes were significantly higher in PRRX1-overexpressing MCF-7 cells compared with those in control cells. Furthermore, relative PTEN expression decreased significantly and levels of phosphorylated PI3K and AKT increased substantially in PRRX1-overexpressing MCF-7 cells. These results indicated that PRRX1 overexpression may induce MDR via PTEN/PI3K/AKT signaling in breast cancer. It is highly recommended that PRRX1 gene expression detection should be performed in patients with breast cancer to aid the selection of more appropriate treatments, which will lead to an improved prognosis in clinical practice.

ERN1 knockdown modifies the effect of glucose deprivation on homeobox gene expressions in U87 glioma cells.

The aim of the present investigation was to study the expression of genes encoding homeobox proteins ZEB2 (zinc finger E-box binding homeobox 2), TGIF1 (TGFB induced factor homeobox 1), SPAG4 (sperm associated antigen 4), LHX1 (LIM homeobox 1), LHX2, LHX6, NKX3-1 (NK3 homeobox 1), and PRRX1 (paired related homeobox 1) in U87 glioma cells in response to glucose deprivation in control glioma cells and cells with knockdown of ERN1 (endoplasmic reticulum to nucleus signaling 1), the major pathway of the endoplasmic reticulum stress signaling, for evaluation of it possible significance in the control of glioma growth through ERN1 signaling and chemoresistance. The expression level of homeobox family genes was studied in control (transfected by vector) and ERN1 knockdown U87 glioma cells under glucose deprivation condition by real-time quantitative polymerase chain reaction. It was shown that the expression level of ZEB2, TGIF1, PRRX1, and LHX6 genes was up-regulated in control glioma cells treated by glucose deprivation. At the same time, the expression level of three other genes (NKX3-1, LHX1, and LHX2) was down-regulated. Furthermore, ERN1 knockdown of glioma cells significantly modified the effect glucose deprivation condition on the expression almost all studied genes. Thus, treatment of glioma cells without ERN1 enzymatic activity by glucose deprivation condition lead to down-regulation of the expression level of ZEB2 and SPAG4 as well as to more significant up-regulation of PRRX1 and TGIF1 genes. Moreover, the expression of LHX6 and NKX3-1 genes lost their sensitivity to glucose deprivation but LHX1 and LHX2 genes did not change it significantly. The results of this investigation demonstrate that ERN1 knockdown significantly modifies the sensitivity of most studied homeobox gene expressions to glucose deprivation condition and that these changes are a result of complex interaction of variable endoplasmic reticulum stress related and unrelated regulatory factors and contributed to glioma cell growth and possibly to their chemoresistance.

PRRX1 isoform PRRX1A regulates the stemness phenotype and epithelial-mesenchymal transition (EMT) of cancer stem-like cells (CSCs) derived from non-small cell lung cancer (NSCLC).

BackgroundsThe 2 isoforms of paired-related homeobox 1 (PRRX1), PRRX1A and PRRX1B, are critical in regulating several kinds of cancers, and figure prominently in the maintenance of stemness and progression of epithelial-mesenchymal transition (EMT). However their differential expression in non-small cell lung cancer (NSCLC) clinical samples and exact regulatory roles in cancer stem-like cells (CSCs) remain unknown.MethodsIn vitro and in vivo experiments were employed to investigate the molecular mechanism. Using CSCs, mouse models, and clinical tissues, we obtained a general picture of the relatively higher level of PRRX1A compared to PRRX1B, and PRRX1A thus promoting EMT and maintaining stemness of CSCs.ResultsPRRX1A but not PRRX1B was upregulated in lung cancer tissues and was positively correlated with TGF-β expression. In CSCs, overexpressed PRRX1A promoted malignant behaviors via transcriptional activation of TGF-β depending on TGF-β/TGF-βR signaling pathway. PRRX1A knockdown decreased self-renewal capacity accompanied by a decrease in stemness factor expression independent of the TGF-β/TGF-βR signaling pathway. Furthermore, PRRX1A was found to tightly bind to and stabilize SOX2. PRRX1A promoted sphere formation not only by enhancing stemness via stabilizing SOX2 but also by promoting cell proliferation.ConclusionsPRRX1A, but not PRRX1B, was demonstrated to have important roles in the regulation of the stemness and metastatic potential of lung cancer, which suggests the potential application of PRRX1A in cancer treatment.

Agnathia-otocephaly complex: a case report and a literature review on recurrence risk

Abstract Objectives Agnathia-otocephaly complex (AOC) is an extremely rare, lethal disorder causing obstruction of the upper airway at birth due to absence of the mandible and hypoplasia of the oral cavity. Implications for future pregnancies need to be elucidated by parental counselling, as recurrence of AOC or associated comorbidities are possible. Very little is known on this subject, because of the rarity of the disorder and scarce data on genetic causes of this complex. The objectives of this study were to determine the recurrence risk and mode of inheritance for AOC based on current literature. Contents Recurrence of AOC or associated comorbidities within the family of an index case was reported in eight articles, describing 7 and 27 relatives, respectively. There were eight AOC cases in which the genetic cause was known. Mutations in 2 genes, orthodenticle homeobox 2 (OTX2) and paired related homeobox 1 (PRRX1), have been described. Due to its mainly sporadic appearance, recurrence risk is low. Counselling on recurrence risk is difficult, because of a broad heterogeneity with complex inheritance patterns and variability in phenotypic expression. Outlook Chromosomal analysis and exome sequencing in children with AOC will help unravel current aetiological uncertainties and could help in further reproductive decisions. We emphasize the need for timely diagnosis through ultrasound, providing parents with the opportunity to receive multidisciplinary counselling, giving them the chance to contemplate their management decisions.

Abstract CN08-02: BMP signaling in glioblastoma

Abstract Glioma-initiating cells (GICs) play central roles in the initiation, progression, recurrence, tumor heterogeneity and drug resistance of glioblastoma. Bone morphogenetic proteins (BMPs) regulate normal embryonic neural development and exert anti-tumor activities in glioblastoma. However, its mechanisms of action remain to be elucidated. Through RNA-seq analyses, we have identified several BMP-target genes in GICs, including SMAD6, Noggin (NOG), Distal-less homeobox 2 (DLX2), and Paired-related homeobox 1 (PRRX1). DLX2 promotes apoptosis and neural differentiation of GICs. We also show that the expression of PRRX1 is induced by BMP stimulation, and that PRRX1 induces decrease in the CD133-positive GIC population and inhibits in vivotumorigenic activity of GICs. Of the two spliced isoforms of PRRX1, the longer form of PRRX1, but not the shorter form, is involved in the induction of differentiation of GICs through epigenetic regulation of the CD133/PROM1gene. In addition, we show that BMP-4 represses the expression of a transmembrane protein, which is preferentially expressed in mesenchymal subtype of glioblastoma. Potential use of these proteins for diagnosis and treatment of glioblastoma will be discussed. Citation Format: Kohei Miyazono, Ryo Tanabe. BMP signaling in glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr CN08-02. doi:10.1158/1535-7163.TARG-19-CN08-02

Aberrant expression of vasculogenic mimicry, PRRX1, and CIP2A in clear cell renal cell carcinoma and its clinicopathological significance

Vasculogenic mimicry (VM) involves a tubular structure with a basement membrane that is similar to and communicates with vessels but functions independent of blood vessels to nourish tumor cells, promote tumor progression, invasion, and metastasis, with reduced 5-year survival rates. Tumor cell proliferation, invasion, and metastasis are promoted by the epithelial-mesenchymal transition (EMT). Paired-related homeobox 1 (PRRX1), a newly discovered EMT inducer, has been shown to correlate with metastasis and prognosis in diverse cancer types. Cancerous inhibitor of protein phosphatase 2A (CIP2A) was initially recognized as an oncoprotein. In this study, we aimed to investigate the expression and clinical significance of the EMT markers PRRX1, CIP2A and VM in clear cell renal cell carcinoma (CCRCC) and their respective associations with clinicopathological parameters and survival.Expression of PRRX1, CIP2A and VM in whole CCRCC tissues from 110 patients was analyzed by immunohistochemical and histochemical staining. Fisher's exact test or the chi square test was used to assess associations with positive or negative staining of these markers and clinicopathological characteristics.Positive expression of CIP2A and VM presence was significantly higher and that of PRRX1 was significantly lower in CCRCC tissues than in corresponding normal tissues. Furthermore, positive expression of CIP2A and VM was significantly associated with tumor grade, size, lymph node metastasis (LNM) stage, and tumor node metastasis (TNM) stage and inversely associated with overall survival time (OST). Moreover, levels of PRRX1 were negatively associated with tumor grade, size, LNM stage, and TNM stage. The PRRX1 subgroup had a significantly longer OST time than did the PRRX1 subgroup. In multivariate analysis, high VM and CIP2A, tumor grade, LNM stage, TNM stage, and low PRRX1 levels were identified as potential independent prognostic factors for OST in CCRCC patients.VM and expression of CIP2A and PRRX1 represent promising biomarkers for metastasis and prognosis and potential therapeutic targets in CCRCC.

Abstract 2857: Vimentin is a novel PKC-ι target facilitating migration and invasion in melanoma

Abstract Vimentin plays an important role in gaining rear-to-front polarity for mesenchymal cells, making it a hallmark of cancer metastasis. Epithelial-mesenchymal transition (EMT) is a vital process in tumor progression that converts stationary epithelial cells into motile mesenchymal phenotype by downregulating E-cadherin and upregulating Vimentin expression. Molecular dynamics of Vimentin intermediate filaments (VIFs) play several key roles in cancer metastasis. Vimentin is activated via phosphorylation through various kinases. Recently, we reported that Protein Kinase C-iota (PKC-ι), activates Vimentin in melanoma while inducing EMT. We also reported the effects of PKC-ι inhibition on mitigating EMT in melanoma based on PKC- ι specific inhibitors {Ratnayake, W.S., et al. Int. J. Oncol. 51(5), (2017), 1370-1382 https://doi.org/10.3892/ijo.2017.4131 and Ratnayake, W.S., et al. Cell Adhes. Migr. (2018) https://doi.org/10.1080/19336918.2018.1471323}. This novel finding is very important with respect to cancer progression since PKC-ι is a well-established oncogene in various tumor types. Here, we analyzed the VIF dynamic changes upon PKC-ι inhibition using specific inhibitors targeting multiple activation sites on Vimentin. In addition to siRNA knockdown of expression of PKC-ι, we also report the effects of siRNA knockdown of two transcription factors, Paired related homeobox1 (PRRX1) and Zinc finger protein SNAI1 (SNAIL1) on the expressions of Vimentin, PKC-ι and E-cadherin. Herein we show that inhibition of PKC-ι downregulate the transcriptional activities of PRRX1 and SNAIL1, which was demonstrated with diminished levels of Vimentin and elevated levels of E-cadherin. Western blot, confocal immunofluorescence and immune-gold electron microscopic results suggested that PKC-ι targets multiple activation sites (S33, S39 and S56) on Vimentin without having an effect on S6 and S71 phosphorylation sites. Results also suggest that PKC-ι inhibition leads to diminution of activities of PRRX1 and SNAIL1 thereby further downregulation of Vimentin while upregulating E-cadherin in order to continue retardation of EMT in-vitro. Overall results indicate that PKC-ι is essential for VIF dynamics regulation during the metastasis in-vitro and therefore can be used as a novel biomarker to assess and mitigate melanoma metastasis. Citation Format: Wishrawana Sarathi Ratnayake, Sloan Breedy, Christopher Apostolatos, Robert Hill, Clare Dennison, Mildred Acevedo-Duncan. Vimentin is a novel PKC-ι target facilitating migration and invasion in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2857.

Expression and prognostic significance of epithelial-mesenchymal transition-related markers and phenotype in serous ovarian cancer

The epithelial-mesenchymal transition (EMT) is known to be associated with carcinoma invasion and metastasis. Previous studies have demonstrated that the expression of EMT-related proteins in carcinoma cells in many organs is associated with a higher histologic grade and a poor prognosis. However, the clinical significance of EMT in ovarian cancers is controversial.Formalin-fixed and paraffin-embedded tumor samples of 198 high-grade serous carcinomas (HGSCs) and 13 serous borderline tumors or low-grade serous carcinomas (SBT/LGSCs) of the ovary were analyzed. EMT phenotype marker expression, including claudin 4, E-cadherin, N-cadherin, α-smooth muscle actin (α-SMA) and vimentin, and EMT related transition factor expression, including paired-related homeobox 1 (PRRX1), SLUG, SNAI1, and TWIST1, were evaluated by immunohistochemistry. EMT phenotype was classified into three groups including complete EMT phenotype, incomplete EMT phenotype, and epithelial phenotype according to epithelial and mesenchymal marker expression.EMT phenotypes varied in HGSC (Complete phenotype, 32.3%; Incomplete phenotype, 42.9%; epithelial phenotype, 24.7%) compared with SBT/LGSC. EMT phenotype and each EMT phenotype markers were not significantly associated with patient survival of HGSCs in multivariate analysis. However transition factor, SLUG expression, correlated with advanced disease and SLUG expression was an independent predictor of poor overall survival in HGSC.EMT related transition factor expression like SLUG is more important in association with clinical outcome than EMT phenotype itself in HGSC.

Paired related homeobox 1 transactivates dopamine D2 receptor to maintain propagation and tumorigenicity of glioma-initiating cells.

Glioblastoma multiforme (GBM) is a highly invasive brain tumor with limited therapeutic means and poor prognosis. Recent studies indicate that glioma-initiating cells/glioma stem cells (GICs/GSCs) may be responsible for tumor initiation, infiltration, and recurrence. GICs could aberrantly employ molecular machinery balancing self-renewal and differentiation of embryonic neural precursors. Here, we find that paired related homeobox 1 (PRRX1), a homeodomain transcription factor that was previously reported to control skeletal development, is expressed in cortical neural progenitors and is required for their self-renewal and proper differentiation. Further, PRRX1 is overrepresented in glioma samples and labels GICs. Glioma cells and GICs depleted with PRRX1 could not propagate in vitro or form tumors in the xenograft mouse model. The GIC self-renewal function regulated by PRRX1 is mediated by dopamine D2 receptor (DRD2). PRRX1 directly binds to the DRD2 promoter and transactivates its expression in GICs. Blockage of the DRD2 signaling hampers GIC self-renewal, whereas its overexpression restores the propagating and tumorigenic potential of PRRX1-depleted GICs. Finally, PRRX1 potentiates GICs via DRD2-mediated extracellular signal-related kinase (ERK) and AKT activation. Thus, our study suggests that therapeutic targeting the PRRX1-DRD2-ERK/AKT axis in GICs is a promising strategy for treating GBMs.

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

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 invitro. 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.

Paired related homeobox 1 is associated with the invasive properties of glioblastoma cells.

Glioblastoma is a highly proliferative and invasive tumor. Despite extensive efforts to develop treatments for glioblastoma, the currently available therapies have only limited effects. To develop novel strategies for glioblastoma treatment, it is crucial to elucidate the molecular mechanisms that promote the invasive properties of glioblastoma. In the present study, we showed that the paired related homeobox 1 (PRRX1) is associated with glioblastoma cell invasion. The depletion of PRRX1 suppressed the invasion and neurosphere formation of glioblastoma cells. Conversely, the exogenous expression of PRRX1 promoted invasion. The Notch signaling pathway, which is an evolutionarily conserved pathway that is essential for developmental processes, plays an important role in the tumorigenesis of glioblastoma. The expression of PRRX1 induced the activation of Notch signaling, and the inhibition of Notch signaling suppressed PRRX1-mediated cell invasion. Our results indicate that activation of Notch signaling by PRRX1 is associated with the promotion of glioblastoma cell invasion.

PRRX1 promotes epithelial-mesenchymal transition through the Wnt/β-catenin pathway in gastric cancer.

Carcinoma cells hijack the epithelial-mesenchymal transition (EMT) for tumor dissemination. Paired-related homeobox 1 (PRRX1) has been identified as a new EMT inducer. However, the function of PRRX1 in gastric cancer has not been elucidated. In this study, we observed that PRRX1 expression levels were upregulated and positively correlated with metastasis and EMT markers in human gastric cancer specimens. PRRX1 overexpression had distinct effects on the cell morphology, proliferation, migration and invasion of BGC823 and SGC7901 gastric cancer cells both in vitro and in xenografts. PRRX1 overexpression resulted in the regulation of the EMT molecular markers N-cadherin, E-cadherin and vimentin as well as the levels of intranuclear β-catenin and the Wnt/β-catenin target c-Myc. Furthermore, the inhibition of the Wnt/β-catenin pathway by XAV939 offset the effects of PRRX1 overexpression. These findings demonstrate that PRRX1 promotes EMT in gastric cancer cells through the activation of Wnt/β-catenin signaling and that PRRX1 upregulation is closely correlated with gastric cancer metastasis.

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

Downregulation of paired related homeobox 1 (PRRX1) is associated with the acquisition of cancer stem cell (CSC)-like properties and poor prognosis in cancers. The purpose of this study is to clarify the role of PRRX1 expression in predicting prognosis and mediating CSC-like properties in hepatocellular carcinoma (HCC). The association between PRRX1 expression and overall survival (OS) of patients with HCC was analyzed in three independent datasets: 62 resected primary cases, 242 cases from GSE14520, and 162 cases from The Cancer Genome Atlas (TCGA). A cell line expressing PRRX1 (HuH7) was established for the functional analyses. The ability to form spheres, the expression levels of the hepatic CSC surface markers (CD13, CD133, and EpCAM), in vitro chemosensitivity to 5-fluorouracil (FU), and radiosensitivity were evaluated. Univariate and multivariate analyses showed that the 5-year OS of the low PRRX1 expression group was significantly poorer than that of the high PRRX1 expression group (P = 0.024 and P = 0.045, respectively). Consistent with this, the low PRRX1 expression group in GSE14520 and TCGA datasets showed significantly shorter OS (P = 0.027 and P = 0.010, respectively). Gene set enrichment analysis on GSE14520 and TCGA datasets indicated that downregulation of PRRX1 was correlated with the stemness signature. The number of spheres and the expression levels of CSC markers were significantly decreased when PRRX1 was expressed. Moreover, PRRX1 impaired resistance to 5-FU and radiation. Downregulation of PRRX1 expression contributes to the poor prognosis of patients with HCC through acquisition of CSC-like properties.