Pancreatic cancer progression relies upon mutant p 53-induced oncogenic signaling mediated by NOP 14

Title Page Title: Pancreatic cancer progression relies upon mutant p53-induced oncogenic signaling mediated by NOP14 Yongxing Du1,, Ziwen Liu , Lei You, Pengjiao Hou, Xiaoxia Ren, Tao Jiao, Wenjing Zhao, Zongze Li, Hong Shu, Changzheng Liu*, Yupei Zhao* 1 Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, PR China 2 Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences,School of Basic Medicine, Peking Union Medical College, Beijing 100005, PR China § Authors share co-first authorship. * To whom correspondence should be addressed: Yupei Zhao, E-mail: zhao8028@263.net, Fax: 86-10-65124875; Changzheng Liu, E-mail: cz-liu@ibms.pumc.edu.cn, Fax: 86-10-65253005. Running Title: NOP14 primes mutp53-driven cancer progression


ABSTRACT
Mutant p53 (mutp53) proteins promote tumor invasion and metastasis in pancreatic ductal adenocarcinoma (PDAC).However, the mechanism underlying sustained activation of mutp53 oncogenic signaling is currently unclear.In this study, we report that NOP14 nucleolar protein (NOP14) expression is upregulated in PDAC tumors and metastatic tissue specimens.
NOP14 overexpression promoted cell motility, whereas NOP14 inhibition decreased invasive capacity of PDAC cells.In vivo invasion assays conducted on established subcutaneously, orthotopically, and intravenously injected tumor mouse models also indicated NOP14 as a promoter of PDAC metastasis.Mechanistically, mutp53 was validated as a functional target of NOP14; NOP14 primed tumor invasion and metastasis by increasing the stability of mutp53 mRNA.The NOP14/mutp53 axis suppressed p21 expression at both the transcriptional and post-transcriptional levels via induction of microRNA-17-5p in PDAC cells.In vivo, high NOP14 expression in PDAC patient tumors correlated with local metastasis and lymph invasion.
Overall, our findings define a novel mechanism for understanding the function of NOP14 in the metastatic cascade of PDAC.Targeting NOP14 allows for effective suppression of tumor invasion in a mutp53-dependent manner, implicating NOP14 inhibition as a potential approach for attenuating metastasis in p53 mutant tumors.

INTRODUCTION
The concept that gain-of-function of mutant p53 (mutp53) proteins led to cancer progression was established over two decades ago, and a number of hotspots have been identified in diverse cancers, including pancreatic ductal adenocarcinoma (PDAC).(1) In human PDAC, p53 accumulation has been correlated with lymph node metastasis, and knock-in Trp53 mutations result in the acquisition of critical functions for overcoming growth arrest/senescence and driving metastasis.(2) Another study has revealed that sustained mutp53 expression is required to maintain the prometastatic phenotype and that platelet-derived growth factor receptor b (PDGFRb) is involved in mutp53-driven PDAC metastasis.(3)These findings indicate that mutp53 is a potential antimetastatic target for PDAC prevention.However, mutp53 proteins have been proven to be undruggable to date.(4)(5) Efforts have been focused on searching for potential mediators of mutp53 activity in cancer progression, and targeting of these related proteins might facilitate the suppression of metastasis driven by mutp53.
NOP14 has been reported to be a nucleolar protein required for maturation of 18S rRNA and for 40S ribosome production.(6) Our preliminary data have revealed that NOP14 causes increased PDAC cell growth and invasion and we have also detected NOP14 mutations in primary and metastatic PDAC tissues, (7)(8) indicating a potential association between NOP14 and cancer invasion.However, the correlation between dysregulated NOP14 and PDAC Herein, we demonstrated that PDAC cells with increased NOP14 expression possess an enhanced invasive capacity.We also showed that NOP14 drives PDAC metastasis by stabilizing mutp53 mRNA, thereby affecting its functional targets.Overall, our data define a mechanism of the NOP14/mutp53 regulatory axis in suppressing P21 expression at both the transcriptional and post-transcriptional levels by induction of microRNA-17-5p (miR-17-5p) in PDAC cells.

Clinical specimens and cell lines
Tissues were collected as previously described.(9) The patient characteristics are provided in Table S1.MIA PaCa-2, Su.86.86,T3M4, PANC-1, SW1990, BxPC-3, and AsPC-1 cell lines were obtained from the American Type Culture Collection (ATCC) and grown in DMEM or RPMI1640 with 10% FBS (HyClone) at 37ºC in 5% CO2 cell culture incubator.Cell lines were tested and authenticated 1 month before the experiment according to microscopic morphology, growth curve analysis, and mycoplasma detection according to the ATCC cell line verification test recommendations.Quantitative real-time PCR (qRT-PCR) analysis was performed using SYBR Green PCR Master Mix with a Bio-Rad IQ5 qRT-PCR system.To determine the miRNA levels, qRT-PCR was conducted using Taqman probes (Invitrogen, Carlsbad, CA, USA) according to the manufacturer′s instructions.The primers are shown in Table S2 and S3.Immunoblotting was performed as described previously.(9) The antibodies used included those against NOP14, p53, PDGFRb, EGFR, TGFB1, SMAD2, ZEB1, P21, and β-actin (p53, ZEB1, EGFR, P21, and β-actin were purchased from CST; and NOP14, PDGFRb, SMAD2, and TGFB1 were obtained from Abcam).

RNA sequencing and data analysis
Directional (stranded) libraries for the paired-end sequencing of PANC-1 cells were generated with an Illumina platform.Differential expression analysis to obtain sequence count data (fragments per kilobase of transcript per million mapped reads [FPKM] values) was conducted using Cuffdiff.

Chromatin immunoprecipitation (ChIP) assay
ChIP assays were performed as previously described.(11)Briefly, protein A/G Sepharose beads conjugated to anti-p53 antibody (Thermo Scientific) were used to immunoprecipitate p53 form whole-cell lysates.performed with an ABI StepOne Plus using SYBR green dye.

PDAC cell-engrafted tumor mouse models
All experimental procedures involving animals were performed according to the institutional ethical guidelines for animal experiments of Peking Union Medical College.

Statistics
Each experiment was repeated at least three times.Student's t test (two-tailed) was performed and three-group data were analyzed using one-way analysis of variance.All statistical analyses were performed using SPSS 16.0 software (SPSS Inc., Chicago, IL, USA).P-values <0.05 were considered statistically significant.NOP14 mutations have been detected in the metastatic nodes of PDAC, suggesting a potential role of NOP14 in PDAC invasion.(8) Here, we examined the function of NOP14 in PDAC metastasis.Thus, IHC analysis was performed to evaluate NOP14 expression in PDAC tissues from 20 patients, which revealed that NOP14 expression was upregulated in the PDAC samples compared with the matched normal controls (Fig. 1A, B).Additionally, NOP14 overexpression was significantly increased in 7 metastases, including 4 hepatic, 2 peritoneum metastases, and 1 lymph node, as shown by IHC analysis (Fig. 1C, D; Table S4).These data indicated that NOP14 expression was positively correlated with PDAC metastasis.To further confirm these findings, NOP14 expression was measured in several PDAC cell lines as shown in Fig. S1A.Further, the invasive capacity of these cells was evaluated by in vitro invasion assays, which showed that PDAC cells with higher NOP14 levels exhibited increased invasiveness (Fig. S1B, C).

Increased
Altogether, these data demonstrate that increased NOP14 expression is associated with enhanced PDAC invasion and metastasis.

NOP14 promotes PDAC cell migration and invasion.
Given the parallels between NOP14 and metastatic potential, we next investigated the role of NOP14 in PDAC cell movement.Thus, we transfected PANC-1 cells with a construct to achieve NOP14 overexpression (Fig. S2A, B).
Then, wound-healing assay was performed, which revealed that NOP14 overexpression led to increased cell migration compared with vector-treated PANC-1 cells (Fig. 1E).We next inhibited NOP14 expression in PANC-1 cells using a specific siRNA (si-NOP14) (Fig. S2C, D) and performed wound-healing assay, which revealed that NOP14 inhibition resulted in reduced wound closure compared with si-Con-treated cells (Fig. 1E).Similar results were observed in MIA PaCa-2 cells (Fig. S3A; Fig. S4).In vitro transwell and invasion assays were employed to further evaluate the impact of NOP14 on PDAC cell movement, which showed that cell migration and invasion was increased by NOP14 overexpression and suppressed by NOP14 inhibition in PANC-1 cells (Fig. 1F).Similar results were observed in MIA PaCa-2 cells (Fig. S3B).
Moreover, the invasive capacity of PDAC cells into collagen gels was determined in inverted invasion assay.We found that NOP14 overexpression enhanced cell invasion and NOP14 inhibition led to decreased invasiveness both in PANC-1 and MIA PaCa-2 cells (Fig. 1G).
Altogether, our data demonstrate that NOP14 overexpression increases PDAC cell migration and invasion.

NOP14 inhibition deceases the invasion of PDAC cell-engrafted tumors.
We next examined the effect of NOP14 on tumor invasion using transplanted tumor mouse models.To this aim, we inhibited NOP14 in PANC-1 cells expressing increased levels of NOP14 and with strong invasiveness using a Lentivirus system expressing siRNA (Lenti-shNOP14) (Fig. S5A, B).Next, Lenti-shNOP14-or Lenti-shCon-infected PANC-1 cells were subcutaneously inoculated into the posterior flanks of nude mice.4  formation, we monitored the growth of transplanted tumors by bioluminescence imaging (BLI) and observed that NOP14 inhibition suppressed the growth of PANC-1-engrafted tumors (Fig. 2A).In agreement with the tumor volumes, the weights of those that were treated with Lenti-shNOP14 were significantly lower than the control tumors (Fig. 2B).
Moreover, we performed H&E and NOP14 staining of randomly selected mouse tumors and observed that NOP14 inhibition resulted in decreased PDAC invasion to adjacent muscle tissues and downregulation of NOP14 expression (Fig. 2C; Fig. S5C).Next, PANC-1 cells infected with Lenti-shNOP14 or Lenti-shCon were orthotopically injected into the pancreas of nude mice.NOP14 inhibition was found to significantly retard the growth of transplanted PANC-1 cells (Fig. 2D).Further, the Lenti-shCon-PANC-1 cells exhibited extensive metastasis, as demonstrated by H&E staining in the dissected tissue samples, whereas the Lenti-shNOP14-PANC-1 cells failed to metastasize to the majority of the examined tissues (Fig. 2E, F).
Altogether, these data indicate that NOP14 inhibition suppresses the invasion of PANC-1-engrafted tumors.

NOP14 inhibition contributes to reduced metastasis of PDAC cells in vivo.
To confirm the above findings, we further conducted in vivo invasion assays.Thus, 5×10 5 viable PANC-1 cells infected with Lenti-shNOP14 or Lenti-shCon were resuspended in 0.1 ml PBS and injected into the lateral tail veins of SCID Lenti-shNOP14-infected PANC-1 cells was found to be decreased compared with that of the Lenti-shCon-infected cells (Fig. 2G).Next, the lungs and livers were dissected for microscopic histological analysis, which revealed extensive metastasis to the lungs in the SCID mice infected with Lenti-shCon-PANC-1 cells (4/5); in addition, NOP14 inhibition significantly decreased the frequency of lung metastasis (1/5), and the lung weights dissected from the Lenti-shNOP14-infected mice were significantly decreased compared with those from the Lenti-shCon-infected mice (Fig. 2H).Further, NOP14 expression was decreased in the examined lung tissues, as demonstrated by IHC analysis (Fig. 2I; Fig. S5D).No significant changes were observed in the outward appearances of the livers (data not shown).
Together, our findings indicate that NOP14 inhibition decreases the metastatic capacity of PDAC cells.

Identification of a gene expression signature of NOP14 induction in PDAC cells.
To identify a genetic signature that may be associated with the NOP14-mediated PDAC metastasis, we performed whole transcriptome RNA-sequencing (RNA-seq) analysis using PANC-1 cells with NOP14 overexpression or inhibition.The expression levels of 144 and 100 genes were found to be positively and negatively correlated with that of NOP14, respectively (Fig. 3A; Table S5).Among these 244 genes, most were involved in physiological regulation (45%) and cellular metabolism (31%), and a few (12%) were involved in cell growth (Fig. 3B).To further narrow down the genes related to PDAC metastasis, those genes from the RNA-seq dataset with at least a 1.5-fold increase or decrease in their expression in PANC-1 cells with NOP14 overexpression or inhibition were selected.A set of 22 genes was validated by qRT-PCR, which indicated that the expression of a number of oncogenes, including PDGFRb, SLUG, ZEB1, EGFR, SMAD2, TWIST1, S100A4, PIM1, and E2F1, was positively regulated by NOP14 and that the expression of several tumor suppressor genes, including TP63, P21, and TP53I3, was negatively regulated by NOP14 in PANC-1 and MIA PaCa-2 cells (Fig. 3C).PANC-1 and MIA PaCa-2 cells carry mutations in p53, and we observed that mutp53 expression was upregulated both in these two cells with NOP14 overexpression, whereas it was downregulated with NOP14 inhibition, as shown by qRT-PCR and immunoblotting analyses (Fig. 3D).
Together, these data indicate that a number of tumor-related genes are involved in NOP14-driven PDAC progression.

NOP14 regulates PDAC metastasis by stabilizing mutp53 mRNA.
Because an alteration in the steady-state level of mutp53 mRNA could be attributed to the induction of either transcription or mRNA degradation by NOP14, we sought to directly explore whether NOP14 inhibition affects the stability of mutp53 mRNA.To this aim, PANC-1 and MIA PaCa-2 cells were treated with ActD to inhibit transcription, which resulted in a decreased mutp53 mRNA half-life in cells with NOP14 inhibition compared with si-Con-treated cells (Fig. 3E).These data indicated that NOP14 enhanced the stability of mutp53 mRNA in PDAC cells.Interestingly, several of the above-mentioned genes have been reported to be direct or indirect effectors of p53 in diverse cancers.(2)(3)(12)(13)(14) To determine whether these genes are regulated by mutp53 in PDAC cells, qRT-PCR and immunoblotting analyses were performed and we found that mutp53 inhibition led to increased expression of P21 and decreased expression of PDGFRb, TGFB1, ZEB1, EGFR, and SMAD2 in PANC-1 and MIA PaCa-2 cells (Fig. 3F; Fig. S6).Further, the expression of EGFR, TGFB1, ZEB1, and SMAD2 were upregulated and downregulated in PANC-1 and MIA PaCa-2 cells with NOP14 overexpression and inhibition, respectively, and P21 expression was negatively regulated by NOP14 in these two cells, as shown by immunoblotting analysis (Fig. 3G).
Although NOP14 overexpression promoted cell invasion in both PANC-1 and MIA PaCa-2 cells, the target genes were not the same, i.e.PDGFRb was regulated by the NOP14/mutp53 axis in MIA PaCa-2 cells but not in PANC-1 cells (Fig. 3G).These discrepancies might be attributed to different p53 mutation sites.
Together, these data demonstrate that NOP14 affects the expression of mutp53 targets by regulating the stability of mutp53 mRNA (Fig. 3H).We further identified the miRNAs induced by NOP14 in PANC-1 cells by miRNA sequencing (miRNA-seq).Analysis of the miRNA-seq data revealed that the expression of 46 miRNAs was induced by NOP14 whereas that of 42 miRNAs was inhibited by NOP14 in PANC-1 cells (Fig. 4A).Among these 88 miRNAs, most were found to be involved in tumorigenesis and progression (55%), cellular metabolism (3%), and immune regulation (1%) (Fig. 4B).Among these cancer-related miRNAs, the expression of miR-17-92 family, miR-31, miR-1244, and miR-4517, was significantly induced by NOP14.To confirm these findings, we performed qRT-PCR using PANC-1 and MIA PaCa-2 cells with NOP14 overexpression or inhibition and found similar alterations in miR-17-5p expression (Fig. 4C, D).Because previous studies have indicated that miR-17-5p promotes cancer metastasis, (15)(16) we next examined whether NOP14 enhances the invasive capacity by inducing miR-17-5p expression in PDAC cells.Thus, we conducted a series of rescue experiments.
Subsequent in vitro transwell and invasion assays revealed that miR-17-5p inhibition to prevent the induction of NOP14 caused decreased cell migration and invasion (Fig. 4F).Further, PANC-1 cells were transfected with miR-17-5p mimic to rescue the downregulated expression of endogenous miR-17-5p induced by NOP14 inhibition (Fig. 4G).Subsequent in vitro transwell and invasion assays indicated that miR-17-5p overexpression to prevent NOP14 inhibition led to increased cell migration and invasion (Fig. 4H).Similar results were observed in MIA PaCa-2 cells subjected to the same treatment (Fig. S7).
Taken together, these data indicate that NOP14 promotes PDAC metastasis at least partly by inducing miR-17-5p expression.

P21 is a direct target of miR-17-5p in PDAC cells
P21 has been reported to be a target of miR-17-5p in diverse cancer cells and in pancreatic cancer stem cells.(17)(18) We further investigated the correlation between miR-17-5p and P21 in PDAC cells.Thus, PANC-1 and MIA PaCa-2 cells were transfected with a p21-3´UTR-wild-type or p21-3´UTR-mutant luciferase reporter, and luciferase activity was assessed, which demonstrated that endogenous miR-17-5p repressed the luciferase activity of the wild-type reporter, whereas mutation of the miR-17-5p sites abrogated this reduction (Fig. 5A, B; Fig. S8).Further, miR-17-5p overexpression resulted in reduced P21 expression, and miR-17-5p inhibition led to upregulation of P21 in PANC-1 and MIA Pa2Ca-2 cells (Fig. 5C).These data indicate that miR-17-5p regulates P21 expression by binding to its complementary sites.NOP14 enhanced miR-17-5p expression in PDAC cells, suggesting that P21 expression might be affected by NOP14.This notion was validated by the above-mentioned findings.Additionally, immunostaining analysis was performed to evaluate P21 expression in PANC-1 cells with miR-17-5p overexpression or inhibition, revealing that miR-17-5p repressed its expression (Fig. 5D).Similar results were observed in PANC-1 cells with NOP14 overexpression or inhibition (Fig. 5E), indicating a positive regulatory association between NOP14 and miR-17-5p.

Research
We also investigated whether P21 was expressed at lower levels in PDAC tissues with upregulated miR-17-5p expression.qRT-PCR was conducted to assess 20 paired PDAC tissues, demonstrating that the miR-17-5p levels were increased in these samples (Fig. 5F).Moreover, P21 expression was significantly downregulated in these specimens, as shown by IHC analysis (Fig. 5G).
Altogether, these findings indicate P21 is a direct target of miR-17-5p in PDAC cells.

NOP14 induces miR-17-5p expression by stabilizing mutp53 mRNA
To explore the mechanism underlying the impact of NOP14 on the upregulation of miR-17-5p in PDAC cells, we first evaluated the RNA stability of primary miR-17-5p (pri-miR-17-5p) in PANC-1 and MIA PaCa-2 cells.We found that NOP14 inhibition did not affect the stability of pri-miR-17-5p in these two cells (Fig. S9).We next assessed whether NOP14 regulates miR-17-5p expression at the transcriptional level.miR-17-92 family has been demonstrated to be a transcriptional target of p53 in colorectal carcinoma and B cell chronic lymphocytic leukemia.(11,19) We showed that NOP14 enhanced the stability of mutp53 mRNA in PDAC cells, as stated above.Thus, we hypothesized that NOP14 induces miR-17-5p expression by stabilizing mutp53 mRNA in PDAC cells.To test this idea, we measured miR-17-5p expression in PANC-1 and MIA PaCa-2 cells with NOP14 inhibition and found that si-NOP14 treatment led to decreased expression of pri-miR-17-5p and miR-17-5p precursor (pre-miR-17-5p), as shown by qRT-PCR (Fig. 6A).We next performed qRT-PCR to evaluate miR-17-5p expression in PANC-1 and MIA PaCa-2 cells with mutp53 inhibition and observed that si-p53 treatment reduced the levels of pri-miR-17-5p and pre-miR-17-5p in these two cells (Fig. 6B).The direct binding of mutp53 to the promoter of miR-17-5p in PANC-1 and MIA PaCa-2 cells was validated by luciferase reporter gene assay and ChIP analysis (Fig. 6C, D).We further transfected NOP14-overexpressing PANC-1 and MIA PaCa-2 cells with si-p53 and found that si-p53 treatment to prevent the induction of NOP14 led to decreased miR-17-5p expression, as shown by qRT-PCR (Fig. 6E).The following rescue assay revealed that miR-17-5p overexpression to prevent the suppression of si-p53 on P21 expression led to increased cell invasion (Fig. 6F, G).

NOP14 expression and PDAC progression
To determine the physiological relevance of NOP14 in PDAC, we performed IHC analysis on sections of PDAC and adjacent normal tissues (Table S6).
Representative NOP14-staining on tissue microarrays (TMAs) containing 90 core pancreatic cancer tissue specimens, including 82 paired PDAC samples, is shown on Fig. 7A.We scored NOP14 expression in the core specimens on a scale from 0 (no expression) to 2 (high expression) based on the IHC scores of NOP14 and observed that NOP14 expression was increased in the PDAC samples (Fig. 7B).These findings are consistent with those obtained for the above-mentioned 20 PDAC tissues.The correlation between NOP14 expression and PDAC progression was further explored, which revealed that PDAC patients with increased NOP14 levels in tumors tended to have tumor invasion and more aggressive tumor phenotypes (Fig. 7C, D, E; Table S6).
Additionally, a higher NOP14 level was found to be correlated with shorter OS, as demonstrated by Kaplan-Meier analysis (P=0.008) (Fig. 7F).
Taken together, these data indicate that increased NOP14 expression is correlated with PDAC development.and miRNA biogenesis.(3,(20)(21)(22) Here, we showed that NOP14 promoted PDAC metastasis by stabilizing mutp53 mRNA in PANC-1 (Trp53 R273H ) and MIA PaCa-2 (Trp53 R248W ) cells.These data suggest that NOP14 acts as a specific regulator of mutp53 and define a novel mechanism for understanding the oncogenic role of mutp53 in tumorigenesis.

Discussion
Given that NOP14 increases the mutp53 protein levels by stabilizing mutp53 mRNA, we proposed that NOP14 might affect mutp53-induced oncogenic signaling.We performed RNA-seq to identify the functional targets of NOP14 involved in PDAC metastasis.A number of protein-encoding genes were verified to be regulated by NOP14.Among them, P21, EGFR, SMAD2, TWIST1, and TP63 are downstream mediators of p53 and these proteins are regulated by mutp53 in PDAC cells, suggesting that NOP14 promotes invasion and metastasis by regulating the stability of mutp53 mRNA, thereby affecting the associated signaling pathways.miRNA-seq data revealed that miR-17-5p expression was significantly regulated by NOP14 in PDAC cells.miR-17-5p has been previously shown to be induced by c-Myc.(23) However, we found that NOP14 did not affect the c-Myc levels in PDAC cells (Fig. S10), indicating that NOP14 regulated miR-17-5p expression through other proteins.Another study has demonstrated that miR-17-5p is negatively regulated by wild-type p53 in HCT116 colon cancer cells.(11) Our data confirmed this finding in PANC-1 and MIA PaCa-2 cells SW1990 cells and revealed that miR-17-5p was regulated by mutp53.Taken together, our results indicate that NOP14 promotes mutp53-driven PDAC metastasis, at least partly through miR-17-5p-mediated P21 signaling.More interestingly, P21 was not only validated as a direct transcriptional target of mutp53, but it was also found to be inhibited by miR-17-5p, demonstrating that the NOP14/mutp53 regulatory axis affects P21 expression at both the transcriptional and post-transcriptional levels.Further analysis of the RNA-seq and miRNA-seq data validated that several tumor-related genes, including TP63 (target of miR-20a and let-7i), BCL2 (target of miR-195 and miR-34), and PDGFRb (target of miR-195), were transcriptional targets of p53 and that these miRNAs were also directly regulated by p53.(3)(4)(24)(25)(26) These results revealed a global mechanism that increased understanding of the influences of the NOP14/mutp53 regulatory axis on its downstream molecules, i.e. the expression of the p53 transcriptional effectors was also found to be regulated by p53-induced miRNAs at the post-transcriptional level (Fig. 6H).
In summary, our data define the function and mechanism of NOP14 in mutp53-driven PDAC metastasis.Thus, targeting of NOP14 may represent a realistic approach for the prevention of PDAC with mutp53.
, 2017.© 2017 American Association for Cancer cancerres.aacrjournals.orgDownloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.Author Manuscript Published OnlineFirst on March 9, 2017; DOI: 10.1158/0008-5472.CAN-16-2339 progression remains unclear, and little else is known about the mechanisms underlying the function of NOP14 in the metastasis of p53 mutant tumors.
Cancer cells expressing mutp53 possess the oncogenic capacity to promote cell proliferation, survival, and metastasis, indicating that targeting mutp53 may be a potential therapeutic strategy for cancer prevention.Because no effective strategies have been validated for the targeting of mutp53, recent studies have focused on elucidating the mechanisms underlying the regulation of mutp53-induced oncogenic signaling.A number of molecules have been identified as potential mediators of mutp53 function in cancer progression, such as PDGFRb, proteins involved in integrin recycling, mevalonate pathway, Research.on November 15, 2017.© 2017 American Association for Cancer cancerres.aacrjournals.orgDownloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.Author Manuscript Published OnlineFirst on March 9, 2017; DOI: 10.1158/0008-5472.CAN-16-2339 , 2017.© 2017 American Association for Cancer cancerres.aacrjournals.orgDownloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.Author Manuscript Published OnlineFirst on March 9, 2017; DOI: 10.1158/0008-5472.CAN-16-2339