Gene Summary

Gene:TP73; tumor protein p73
Aliases: P73
Summary:This gene encodes a member of the p53 family of transcription factors involved in cellular responses to stress and development. It maps to a region on chromosome 1p36 that is frequently deleted in neuroblastoma and other tumors, and thought to contain multiple tumor suppressor genes. The demonstration that this gene is monoallelically expressed (likely from the maternal allele), supports the notion that it is a candidate gene for neuroblastoma. Many transcript variants resulting from alternative splicing and/or use of alternate promoters have been found for this gene, but the biological validity and the full-length nature of some variants have not been determined. [provided by RefSeq, Feb 2011]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tumor protein p73
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Breast CancerTP73 and Breast Cancer View Publications15
Lung CancerTP73 and Lung Cancer View Publications11
NeuroblastomaTP73 and Neuroblastoma
TP73 was a candidate tumour suppresser gene for neuroblastoma given that a) the gene is homologous to TP53 and b) TP73 is located in the 1p36 region which is frequently deleted in neuroblastoma. However, research suggests that TP73 is infrequently mutated in neuroblastoma; in a study including tumours detected by mass screening (Ichimiya et al, 1999) only 2 out of 140 neuroblastomas had TP73 mutations; though LOH for TP73 was seen in 19% of tumours with LOH more frequent in neuroblastomas which were sporadic (not detected by screening), MYCN amplified, and advanced stages. While TP73 may not be a classic Knudson's type tumour supressor gene for neuroblastoma its role in the disease remains to be clarified.
View Publications7
Bladder CancerTP73 Overexpression in Bladder Cancer View Publications4

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: TP73 (cancer-related)

Zhu D, Zhou J, Liu Y, et al.
LncRNA TP73-AS1 is upregulated in non-small cell lung cancer and predicts poor survival.
Gene. 2019; 710:98-102 [PubMed] Related Publications
The present study was carried out to investigate the role of lncRNA TP73-AS1 in non-small cell lung cancer (NSCLC). We found that TP73-AS1 was upregulated in tumor tissues than in non-tumor tissues of NSCLC patients, and high expression levels of TP73-AS1 predicted poor survival. MiR-21 was also upregulated in tumor tissues and positively correlated with TP73-AS1. TP73-AS1 overexpression led to miR-21 upregulation, while miR-21 overexpression failed to affect TP73-AS1. TP73-AS1 and miR-21 overexpression caused the accelerated invasion and migration of NSCLC cells. However, TP73-AS1 overexpression failed to affect cell proliferation. Therefore, TP73-AS1 may upregulate miR-21 to promote NSCLC cell migration and invasion.

Oue N, Sentani K, Sakamoto N, et al.
Molecular carcinogenesis of gastric cancer: Lauren classification, mucin phenotype expression, and cancer stem cells.
Int J Clin Oncol. 2019; 24(7):771-778 [PubMed] Related Publications
Gastric cancer (GC), one of the most common human cancers, is a heterogeneous disease with different phenotypes, prognoses, and responses to treatment. Understanding the pathogenesis of GC at the molecular level is important for prognosis prediction and determining treatments. Microsatellite instability (MSI), silencing of MLH1, MGMT, and CDKN2A genes by DNA hypermethylation, KRAS mutation, APC mutation, and ERBB2 amplification are frequently found in intestinal type GC. Inactivation of CDH1 and RARB by DNA hypermethylation, and amplification of FGFR and MET, are frequently detected in diffuse type GC. In addition, BST2 and PCDHB9 genes are overexpressed in intestinal type GC. Both genes are associated with GC progression. GC can be divided into gastric/intestinal mucin phenotypes according to mucin expression. MSI, alterations of TP73, CDH1 mutation, and DNA methylation of MLH are detected frequently in the gastric mucin phenotype. TP53 mutation, deletion of APC, and DNA methylation of MGMT are detected frequently in the intestinal mucin phenotype. FKTN is overexpressed in the intestinal mucin phenotype, and IQGAP3 is overexpressed in the gastric mucin phenotype. These genes are involved in GC progression. To characterize cancer stem cells, a useful method is spheroid colony formation. KIFC1 and KIF11 genes show more than twofold higher expression in spheroid-forming cells than that in parental cells. Both KIF genes are overexpressed in GC, and knockdown of these genes inhibits spheroid formation. Alterations of these molecules may be useful to understand gastric carcinogenesis. Specific inhibitors of these molecules may also be promising anticancer drugs.

Zhang Q, Di C, Yan J, et al.
Inhibition of SF3b1 by pladienolide B evokes cycle arrest, apoptosis induction and p73 splicing in human cervical carcinoma cells.
Artif Cells Nanomed Biotechnol. 2019; 47(1):1273-1280 [PubMed] Related Publications
Pladienolide B is a potent cancer cell growth inhibitor that targets the SF3b1 subunit of the spliceosome. There is considerable interest in the compound as a tool to study SF3b1 function in cancer. However, so far little information is available on the molecular mechanism of SF3b1 eliciting apoptosis in cancer cells. Here, we investigated the molecular mechanism of SF3b1 eliciting apoptosis in human cervical carcinoma cells. We demonstrated that inhibition of SF3b1 by pladienolide B inhibited proliferation of HeLa cells at low nanomolar concentrations in a dose- and time-dependent manner. It also induced G2/M phase arrest and significant rise of apoptotic cells. Moreover, it is indicated that inhibition of SF3b1 by pladienolide B induced Tap73/ΔNp73 expression and consequently down-regulated Bax/Bcl-2 ratio, cytochrome c release and caspase-3 expression. Thus, our results showed that SF3b1 plays a pivotal role in cycle arrest, apoptosis induction, and p73 splicing in human cervical carcinoma cells, suggesting that SF3b1 could be used as a potential candidate for cervical cancer therapy.

Logotheti S, Marquardt S, Pützer BM
p73-Governed miRNA Networks: Translating Bioinformatics Approaches to Therapeutic Solutions for Cancer Metastasis.
Methods Mol Biol. 2019; 1912:33-52 [PubMed] Related Publications
The transcription factor p73 synthesizes a large number of isoforms and presents high structural and functional homology with p53, a well-known tumor suppressor and a famous "Holy Grail" of anticancer targeting. p73 has attracted increasing attention mainly because (a) unlike p53, p73 is rarely mutated in cancer, (b) some p73 isoforms can inhibit all hallmarks of cancer, and (c) it has the ability to mimic oncosuppressive functions of p53, even in p53-mutated cells. These attributes render p73 and its downstream pathways appealing for therapeutic targeting, especially in mutant p53-driven cancers. p73 functions are, at least partly, mediated by microRNAs (miRNAs), which constitute nodal components of p73-governed networks. p73 not only regulates transcription of crucial miRNA genes, but is also predicted to affect miRNA populations in a transcription-independent manner by developing protein-protein interactions with components of the miRNA processing machinery. This combined effect of p73, both in miRNA transcription and maturation, appears to be isoform-dependent and can result in a systemic switch of cell miRNomes toward either an anti-oncogenic or oncogenic outcome. In this review, we combine literature search with bioinformatics approaches to reconstruct the p73-governed miRNA network and discuss how these crosstalks may be exploited to develop next-generation therapeutics.

Hong S, Xu J, Li Y, et al.
Topoisomerase IIβ-binding protein 1 activates expression of E2F1 and p73 in HPV-positive cells for genome amplification upon epithelial differentiation.
Oncogene. 2019; 38(17):3274-3287 [PubMed] Free Access to Full Article Related Publications
High-risk human papillomaviruses (HPVs) constitutively activate ataxia telangiectasia mutated (ATM) and ataxia telangiectasia- and Rad3-related (ATR) DNA damage repair pathways for viral genome amplification. HPVs activate these pathways through the immune regulator STAT-5. For the ATR pathway, STAT-5 increases expression of the topoisomerase IIβ-binding protein 1 (TopBP1), a scaffold protein that binds ATR and recruits it to sites of DNA damage. TopBP1 also acts as a transcriptional regulator, and we investigated how this activity influenced the HPV life cycle. We determined that TopBP1 levels are increased in cervical intraepithelial neoplasias as well as cervical carcinomas, consistent with studies in HPV-positive cell lines. Suppression of TopBP1 by shRNAs impairs HPV genome amplification and activation of the ATR pathway but does not affect the total levels of ATR and CHK1. In contrast, knockdown reduces the expression of other DNA damage factors such as RAD51 and Mre11 but not BRCA2 or NBS1. Interestingly, TopBP1 positively regulates the expression of E2F1, a TopBP1-binding partner, and p73 in HPV-positive cells in contrast to its effects in other cell types. TopBP1 transcriptional activity is regulated by AKT, and treatment with AKT inhibitors suppresses expression of E2F1 and p73 without interfering with ATR signaling. Importantly, the levels of p73 are elevated in HPV-positive cells and its knockdown impairs HPV genome amplification. This demonstrates that p73, like p63 and p53, is an important regulator of the HPV life cycle that is controlled by the transcriptional activating properties of the multifunctional TopBP1 protein.

Zhu L, Li XX, Shi L, et al.
Rapamycin enhances the sensitivity of ER‑positive breast cancer cells to tamoxifen by upregulating p73 expression.
Oncol Rep. 2019; 41(1):455-464 [PubMed] Related Publications
A total of 70% of breast cancers express the estrogen receptor (ER)α; therefore, targeting the ER may be an effective endocrine therapy with which to inhibit breast cancer growth. Tamoxifen is the most common‑used clinically used drug for the treatment of advanced or metastatic ER‑positive (ER+) breast cancer. However, a substantial proportion of patients become resistant to endocrine therapies. To overcome this limitation, in this stud, we sought to maximize the benefits associated with tamoxifen therapy via drug combination strategies. We demonstrated that rapamycin, an FDA‑approved mammalian target of rapamycin (mTOR) inhibitor, enhanced the effects of endocrine therapy with tamoxifen, and the concentration of tamoxifen required for ER+ breast cancer cell growth inhibition was substantially reduced. Moreover, treatment with rapamycin plus tamoxifen significantly inhibited tumor growth in vivo. In addition, this synergistic effect may be mediated by the induction of p73. We revealed a novel mechanism in which p73 increases ERα expression by directly binding to the promoter region of the ERα gene. Taken together, the findings of this study indicate that combination therapy with rapamycin and tamoxifen underlying p73‑mediated ERα expression may provide new insight into the drug combination for the treatment of ER+ breast cancer.

Liu C, Ren L, Deng J, Wang S
LncRNA TP73-AS1 promoted the progression of lung adenocarcinoma via PI3K/AKT pathway.
Biosci Rep. 2019; 39(1) [PubMed] Free Access to Full Article Related Publications
Lung adenocarcinoma (LAD) is one of the most common malignancies that threats human health worldwide. Long non-coding RNAs (lncRNAs) have been reported to play significant roles in tumorigenesis and might be novel biomarkers and targets for diagnosis and treatment of cancers. TP73-AS1 is a newly discovered lncRNA involved in the tumorigenesis and development of several cancers. However, its role in LAD has not been investigated yet. In the present study, we first found that TP73-AS1 expression was markedly increased in LAD tissues and cell lines and its overexpression was strongly associated with poor clinical outcomes. Then the loss/gain-of-function assays elucidated that TP73-AS1 contributed to cell proliferation, migration, and invasion

Zhang X, Abdelrahman A, Vollmar B, Zechner D
The Ambivalent Function of YAP in Apoptosis and Cancer.
Int J Mol Sci. 2018; 19(12) [PubMed] Free Access to Full Article Related Publications
Yes-associated protein, a core regulator of the Hippo-YAP signaling pathway, plays a vital role in inhibiting apoptosis. Thus, several studies and reviews suggest that yes-associated protein is a good target for treating cancer. Unfortunately, more and more evidence demonstrates that this protein is also an essential contributor of p73-mediated apoptosis. This questions the concept that yes-associated protein is always a good target for developing novel anti-cancer drugs. Thus, the aim of this review was to evaluate the clinical relevance of yes-associated protein for cancer pathophysiology. This review also summarized the molecules, processes and drugs, which regulate Hippo-YAP signaling and discusses their effect on apoptosis. In addition, issues are defined, which should be addressed in the future in order to provide a solid basis for targeting the Hippo-YAP signaling pathway in clinical trials.

Ji H, Huang C, Wu S, Kasim V
XBP1-s promotes colorectal cancer cell proliferation by inhibiting TAp73 transcriptional activity.
Biochem Biophys Res Commun. 2019; 508(1):203-209 [PubMed] Related Publications
Endoplasmic reticulum (ER) stress activation could be found in a wide range of human tumors. ER stress induces the splicing of X-box binding protein 1 (XBP1) to form its splicing variant XBP1-s, which in turn activates various ER stress-related genes. XBP1-s is highly expressed in various tumors; however, its role in tumorigenesis is still largely unknown. Herein we showed that XBP1-s suppresses the expression of tumor suppressor TAp73, a member of p53 family with high homology with p53, by directly binds to TAp73 promoter and suppresses its transcriptional activity. We also found that overexpression of TAp73 cancelled the effect of XPB1-s on enhancing colorectal cancer cells proliferation and colony formation potential, indicating that TAp73 is critical for XBP1-s-induced tumorigenesis. Together, our findings not only reveal a novel mechanism of TAp73 aberrant regulation in tumor cells, but also link up tumor cells ER stress with tumor suppressive activity of TAp73.

Jia Z, Peng J, Yang Z, et al.
Long non-coding RNA TP73‑AS1 promotes colorectal cancer proliferation by acting as a ceRNA for miR‑103 to regulate PTEN expression.
Gene. 2019; 685:222-229 [PubMed] Related Publications
There is an increasing evidence that long non-coding RNAs (lncRNAs) play an important role in tumorigenesis and cancer progression. This study focused on the functional role of P73 antisense RNA 1T (TP73‑AS1), a lncRNA, in colorectal cancer (CRC). We found that TP73‑AS1 expression was significantly low in CRC tissues and cells, and high TP73‑AS1 expression was negatively associated with TNM stage, prognosis, overall survival, and disease-free survival in the CRC patients. Moreover, TP73‑AS1 overexpression dramatically inhibited CRC cell growth, promoted apoptosis, downregulated Bcl‑2 levels, and increased caspase‑3 expression. Furthermore, TP73‑AS1 expression levels were positively associated with PTEN levels in clinical CRC samples. As expected, TP73‑AS1 could upregulate PTEN expression in CRC cells. Mechanistically, PTEN was shown to be the target of miR‑103. Interestingly, TP73‑AS1 overexpression could increase PTEN expression through competitive binding to miR‑103. Functionally, our data show that such TP73‑AS1-induced PTEN expression through binding to miR‑103 facilitated CRC cell proliferation. Thus, we showed that TP73‑AS1 inhibits CRC cell growth by functioning as a ceRNA (competing endogenous RNAs) to regulate PTEN levels. Our findings provide new insights into the underlying molecular mechanisms of TP73‑AS1-mediated CRC.

Safaroghli-Azar A, Bashash D, Kazemi A, et al.
Anticancer effect of pan-PI3K inhibitor on multiple myeloma cells: Shedding new light on the mechanisms involved in BKM120 resistance.
Eur J Pharmacol. 2019; 842:89-98 [PubMed] Related Publications
The correlation between the Phosphoinositide 3-kinase (PI3K) axis and crucial mechanisms involved in the maintenance of the neoplastic nature of multiple myeloma (MM) has recently evolved a general agreement that PI3K inhibition-based therapies could construct an exciting perspective for the future treatment strategies. Our results outlined that abrogation of PI3K using pan-PI3K inhibitor BKM120 decreased survival of MM cells through induction of a caspase-3-dependent apoptosis coupled with SIRT1-mediated G2/M arrest in both KMM-1 and RPMI 8226 cell lines; however, the cell responses to the inhibitor was quite different, introducing wild-type PTEN-expressing RPMI 8226 as less sensitive cells. By investigating the sensitivity extent of a panel of hematological cell lines to BKM120, we found no significant association with respect to PTEN status. As far as we are aware, the results of the present study propose for the first time that the inhibitory effect of BKM120 was overshadowed, at least partially, through over-expression of either c-Myc or nuclear factor (NF)-κB in less sensitive MM cells. While there was no significant effect of the inhibitor on the expression of c-Myc in RPMI 8226, we found an enhanced cytotoxic effect when BKM120 was used in combination with a small molecule inhibitor of c-Myc. Noteworthy, the results of the synergistic experiments also revealed that BKM120 could produce a synergistic anti-cancer effect with carfilzomib (CFZ) and provided an enhanced therapeutic efficacy in MM cells, highlighting that PI3K inhibition might be a befitting approach in MM both in mono and combined therapy.

Kumar S, Talluri S, Pal J, et al.
Role of apurinic/apyrimidinic nucleases in the regulation of homologous recombination in myeloma: mechanisms and translational significance.
Blood Cancer J. 2018; 8(10):92 [PubMed] Free Access to Full Article Related Publications
We have previously reported that homologous recombination (HR) is dysregulated in multiple myeloma (MM) and contributes to genomic instability and development of drug resistance. We now demonstrate that base excision repair (BER) associated apurinic/apyrimidinic (AP) nucleases (APEX1 and APEX2) contribute to regulation of HR in MM cells. Transgenic as well as chemical inhibition of APEX1 and/or APEX2 inhibits HR activity in MM cells, whereas the overexpression of either nuclease in normal human cells, increases HR activity. Regulation of HR by AP nucleases could be attributed, at least in part, to their ability to regulate recombinase (RAD51) expression. We also show that both nucleases interact with major HR regulators and that APEX1 is involved in P73-mediated regulation of RAD51 expression in MM cells. Consistent with the role in HR, we also show that AP-knockdown or treatment with inhibitor of AP nuclease activity increases sensitivity of MM cells to melphalan and PARP inhibitor. Importantly, although inhibition of AP nuclease activity increases cytotoxicity, it reduces genomic instability caused by melphalan. In summary, we show that APEX1 and APEX2, major BER proteins, also contribute to regulation of HR in MM. These data provide basis for potential use of AP nuclease inhibitors in combination with chemotherapeutics such as melphalan for synergistic cytotoxicity in MM.

Rahman FU, Bhatti MZ, Ali A, et al.
Dimetallic Ru(II) arene complexes appended on bis-salicylaldimine induce cancer cell death and suppress invasion via p53-dependent signaling.
Eur J Med Chem. 2018; 157:1480-1490 [PubMed] Related Publications
A series of bis-salicylaldimine ligands bearing two ON-donor functions were reacted with dichloro(p-cymene)ruthenium(II) dimer in the presence of base (NaOAc) and a series of four dimetallic Ru(II) arene complexes (Ru(p-cymene))

Ding Z, Lan H, Xu R, et al.
LncRNA TP73-AS1 accelerates tumor progression in gastric cancer through regulating miR-194-5p/SDAD1 axis.
Pathol Res Pract. 2018; 214(12):1993-1999 [PubMed] Related Publications
BACKGROUND: Long noncoding RNAs (lncRNAs) have been considered as significant regulators in many cancer progression, such as proliferation, invasion and other path of evolution. Nevertheless, we have not had a grasp of the role of lncRNA TP73-AS1 in gastric cancer (GC).
METHODS: qRT-PCR analysis was first conducted to examine the TP73-AS1 level in both GC tissues and cell lines. Then gain or loss-of-function assays were carried out to detect the effect of TP73-AS1 on GC development. In mechanism, bioinformatics analysis and luciferase reporter assays were used to search and confirm the target gene of TP73-AS1. Finally, rescue assays were performed to confirm the influence of TP73-AS1-miR-194-5p-SDAD1 axis on GC development.
RESULTS: TP73-AS1 was upregulated in GC tissues and cell lines. Furthermore, TP73-AS1 exerted oncogenic role in GC through promoting cell growth and metastasis. In addition, TP73-AS1 was certified as a ceRNA by regulating miR-194-5p/SDAD1 axis.
CONCLUSIONS: TP73-AS1 accelerates tumor progression in gastric cancer through regulating miR-194-5p/SDAD1 axis.

Wang X, Chen H, Wen Y, et al.
Dicer affects cisplatin‑mediated apoptosis in epithelial ovarian cancer cells.
Mol Med Rep. 2018; 18(5):4381-4387 [PubMed] Free Access to Full Article Related Publications
Dicer is an essential enzyme that processes micro (mi)-RNA precursors into mature miRNAs, and serves a critical role in cancer development and progression by regulating gene expression. However, the role of Dicer in cisplatin‑mediated apoptosis and chemotherapy resistance in epithelial ovarian cancer (EOC) cells is poorly understood. In the present study, Dicer was expressed at low levels in cisplatin‑resistant A2780 cells when compared with parental cells. In addition, knocking down Dicer using short hairpin RNA decreased the sensitivity of A2780 and CAOV3 cells to cisplatin. Furthermore, downregulating Dicer significantly inhibited cisplatin‑induced apoptosis in ovarian cancer cells, and decreased the levels of proteins involved in apoptosis signaling pathways, including P73, P63, P53, caspase‑9 and caspase‑3. These findings indicated that Dicer may be a promising target for overcoming drug resistance in ovarian cancer.

Funato K, Hayashi T, Echizen K, et al.
SIRT2-mediated inactivation of p73 is required for glioblastoma tumorigenicity.
EMBO Rep. 2018; 19(11) [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Glioblastoma is one of the most aggressive forms of cancers and has a poor prognosis. Genomewide analyses have revealed that a set of core signaling pathways, the p53, RB, and RTK pathways, are commonly deregulated in glioblastomas. However, the molecular mechanisms underlying the tumorigenicity of glioblastoma are not fully understood. Here, we show that the lysine deacetylase SIRT2 is required for the proliferation and tumorigenicity of glioblastoma cells, including glioblastoma stem cells. Furthermore, we demonstrate that SIRT2 regulates p73 transcriptional activity by deacetylation of its C-terminal lysine residues. Our results suggest that SIRT2-mediated inactivation of p73 is critical for the proliferation and tumorigenicity of glioblastoma cells and that SIRT2 may be a promising molecular target for the therapy of glioblastoma.

Bibi F, Ali I, Naseer MI, et al.
Detection of genetic alterations in gastric cancer patients from Saudi Arabia using comparative genomic hybridization (CGH).
PLoS One. 2018; 13(9):e0202576 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: The present study was conducted to discover genetic imbalances such as DNA copy number variations (CNVs) associated with gastric cancer (GC) and to examine their association with different genes involved in the process of gastric carcinogenesis in Saudi population.
METHODS: Formalin-fixed paraffin-embedded (FFPE) tissues samples from 33 gastric cancer patients and 15 normal gastric samples were collected. Early and late stages GC samples were genotyped and CNVs were assessed by using Illumina HumanOmni1-Quad v.1.0 BeadChip.
RESULTS: Copy number gains were more frequent than losses throughout all GC samples compared to normal tissue samples. The mean number of the altered chromosome per case was 64 for gains and 40 for losses, and the median aberration length was 679115bp for gains and 375889bp for losses. We identified 7 high copy gain, 52 gains, 14 losses, 32 homozygous losses, and 10 copy neutral LOHs (loss of heterozygosities). Copy number gains were frequently detected at 1p36.32, 1q12, 1q22, 2p11.1, 4q23-q25, 5p12-p11, 6p21.33, 9q12-q21.11, 12q11-q12, 14q32.33, 16p13.3, 17p13.1, 17q25.3, 19q13.32, and losses at 1p36.23, 1p36.32, 1p32.1, 1q44, 3q25.2, 6p22.1, 6p21.33, 8p11.22, 10q22.1, 12p11.22, 14q32.12 and 16q24.2. We also identified 2 monosomy at chromosome 14 and 22, 52 partially trisomy and 22 whole chromosome 4 neutral loss of heterozygosities at 13q14.2-q21.33, 5p15.2-p15.1, 5q11.2-q13.2, 5q33.1-q34 and 3p14.2-q13.12. Furthermore, 11 gains and 2 losses at 1p36.32 were detected for 11 different GC samples and this region has not been reported before in other populations. Statistical analysis confirms significant association of H. pylori infection with T4 stage of GC as compare to control and other stages.
CONCLUSIONS: We found that high frequency of copy number gains and losses at 1p36.23, 1p32.1, 1p36.32, 3q25.2, 6p21.33 and 16q24.2 may be common events in gastric cancer. While novel CNVs at 1p36.32 harbouring PRDM16, TP73 and TP73-AS1 genes showed 11 gains and 2 losses for 11 different GC cases and this region is not reported yet in Database of Genomic Variants may be specific to Saudi population.

Tao W, Sun W, Zhu H, Zhang J
Knockdown of long non-coding RNA TP73-AS1 suppresses triple negative breast cancer cell vasculogenic mimicry by targeting miR-490-3p/TWIST1 axis.
Biochem Biophys Res Commun. 2018; 504(4):629-634 [PubMed] Related Publications
Triple negative breast cancer (TNBC) is among the most clinically aggressive subtypes of breast cancer. Despite the availability of new drugs, patients suffering TNBC bear disheartening prognosis. Vasculogenic mimicry (VM) is a malignant tumor specific non-endothelial vascular network, which provide oxygen and nutrients to tumor cells and facilitate tumor progression. Therefore targeting TNBC VM formation may contribute to tumor treatment. In this study, we found that long non-coding RNA TP73 antisense RNA 1 (TP73-AS1) was upregulated in VM positive TNBC tissues. Knockdown of TP73-AS1 suppressed TNBC cell line MDA-MB-231 cell VM formation in vitro. In addition, RNA immunoprecipitation assay and dual luciferase reporter assay showed that TP73-AS1 bound to miR-490-3p in a sequence-specific manner. miR-490-3p was downregulated in VM positive tissues and was involved in TP73-AS1-mediated MDA-MB-231 cell VM formation. Furthermore, TWIST1 was a target of miR-490-3p and participated in TP73-AS1/miR-490-3p-modulated MDA-MB-231 cell VM formation. Findings in this study may provide insight in TNBC management.

Zhang W, Zhai Y, Wang W, et al.
Enhanced expression of lncRNA TP73-AS1 predicts unfavorable prognosis for gastric cancer and promotes cell migration and invasion by induction of EMT.
Gene. 2018; 678:377-383 [PubMed] Related Publications
Gastric cancer (GC) is a deadly disease with high incidence worldwide in recent years. Long noncoding RNAs (lncRNAs) were found to play imperative roles in many biological processes, such as cancer development and progression. Specifically, TP73-AS1, a novel cancer-related lncRNA, was documented to be up-regulated in several malignancies, but the clinical significance and functional role of TP73-AS1 in GC is still unknown. RT-qPCR was performed to evaluate TP73-AS1 transcription in GC tissue specimens and cell lines. In addition, the correlation between TP73-AS1 transcription and clinicopathologic features was further evaluated. Moreover, the effects of TP73-AS1 on GC cell were measured in vitro and in vivo. The data documented that TP73-AS1 was enhanced in GC tissues and cells, and TP73-AS1 transcription level was tightly associated with tumor size, TNM stage, and overall survival in 76 GC patients. What's more, decreased TP73-AS1 could restrain cell growth and colony-forming capacity and promoted apoptosis partly by regulating Bcl-2/caspase-3 pathway. Importantly, TP73-AS1 could promote xenograft growth in vivo. Silencing of TP73-AS1 inhibited GC cell migratory and invasive properties partly by reversing snail-mediated epithelial-to-mesenchymal transition (EMT). Collectively, this study may help to develop the treatment strategy for GC.

Zhang X, Zhang M, Wang G, et al.
Tumor promoter role of miR‑647 in gastric cancer via repression of TP73.
Mol Med Rep. 2018; 18(4):3744-3750 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
It has previously been demonstrated that miRNA (miR)‑647 exhibits an important role in various cancers, and is aberrantly expressed in gastric cancer (GC). However, the exact role of miR‑647 in GC still remains unclear. The present study aimed to investigate the functional significance of miR‑647 and its target gene in GC. TargetScan and Miranda databases were used to predict the putative targets, and the prediction was validated by Dual‑luciferase Reporter Assays. To investigate whether miR‑647 affects GC cell behavior, a stable miR‑647‑overexpression/low‑expression cell line was generated by transfection with miR‑647 mimic/inhibitor. MTT, Flow Cytometry and Transwell invasion assays were performed to investigate the proliferation, cell apoptosis, migration and invasion properties of MGC‑803 cells. Additionally, reverse transcription‑quantitative polymerase chain reaction and western blot analysis were performed to detect the mRNA and protein expression levels of the apoptosis‑associated genes. The results suggested that tumor protein P73 (TP73) is a target gene of miR‑647. TP73 was markedly decreased following miR‑647 overexpression and significantly increased following miR‑647 inhibition. Following overexpression of miR‑647, the proliferation, migration and invasion of MGC‑803 cells were significantly increased, whereas the percentage of apoptotic cells decreased. Conversely, the proliferation, migration and invasion of MGC‑803 cells were significantly declined, and the percentage of apoptotic cells increased following miR‑647 inhibition. In addition, the B cell lymphoma (Bcl)‑2 Associated X, Apoptosis Regulator/Bcl‑2 ratio was markedly decreased when miR‑647 was overexpressed by miRNA mimics, and significantly increased when miR‑647 expression was inhibited via an miRNA inhibitor. Overall, miR‑647 functions as a tumor promoter in GC by repressing TP73.

Liu G, Zhao X, Zhou J, et al.
LncRNA TP73-AS1 Promotes Cell Proliferation and Inhibits Cell Apoptosis in Clear Cell Renal Cell Carcinoma Through Repressing KISS1 Expression and Inactivation of PI3K/Akt/mTOR Signaling Pathway.
Cell Physiol Biochem. 2018; 48(1):371-384 [PubMed] Related Publications
BACKGROUND/AIMS: Emerging evidence suggests that long non-coding RNAs (lncRNAs) play a vital regulatory role in the pathogenesis and progression of renal cell carcinoma (RCC). We aim to determine lncRNA profiles in clear cell RCC (ccRCC) and investigate key lncRNAs involved in ccRCC tumorigenesis and progression.
METHODS: RNA sequencing technique and qPCR were used to determine the candidate lncRNAs in ccRCC tissues. The correlations between lncRNA P73 antisense RNA 1T (TP73-AS1) levels and survival outcomes were analyzed to elucidate its clinical significance. The underlying mechanisms of TP73-AS1 in ccRCC were analyzed through in vitro functional assays.
RESULTS: We found TP73-AS1 was upregulated in 40 ccRCC tissues compared with adjacent normal renal tissues and increased TP73-AS1 was correlated to aggressive clinicopathologic features and unfavorable prognosis. Knockdown of TP73-AS1 suppressed cell proliferation, invasion and induced cell apoptosis. We also identified KISS-1 metastasis-suppressor (KISS1) was significantly upregulated in TP73-AS1 knockdown cells. Further, we revealed that TP73-AS1 suppressed KISS1 expression through the interaction with Enhancer of zeste homolog 2 (EZH2) and the specific binding to KISS1 gene promoter region. Knockdown of KISS1 partly reversed TP73-AS1 knockdown-induced inhibition of cell proliferation and promotion of apoptosis. We further determined that TP73-AS1 knockdown activated PI3K/Akt/mTOR signaling pathway, while overexpression of TP73-AS1 induced inhibition of PI3K/Akt/mTOR pathway and these effects could be partly abolished by overexpression of KISS1.
CONCLUSION: In conclusion, we identified that TP73-AS1 as an oncogenic lncRNA in the development of ccRCC and a potential target for human renal carcinoma treatment.

Cai Y, Yan P, Zhang G, et al.
Long non-coding RNA TP73-AS1 sponges miR-194 to promote colorectal cancer cell proliferation, migration and invasion via up-regulating TGFα.
Cancer Biomark. 2018; 23(1):145-156 [PubMed] Related Publications
OBJECTIVE: Colorectal cancer (CRC) is the 3rd most common cancer worldwide. Recently, long non-coding RNAs (lncRNAs) were found to be critical modulators in the CRC progression. The aim of this study is to investigate the potential roles of lncRNA P73 antisense RNA 1T (TP73-AS1) in CRC development and progression.
METHODS: Quantitative real-time PCR (qRT-PCR) was performed to determine relevant gene expression levels; western blot was performed to determine protein expression levels; CCK-8, colony formation, wound healing and Transwell invasion assays were used to determined CRC cell proliferation, migration and invasion; in vivo tumor growth was assessed in xenograft mice model.
RESULTS: TP73-AS1 was up-regulated in both CRC tissues and CRC cell lines. Overexpression of TP73-AS1 was associated with metastasis and advanced clinical stages in CRC patients. Overexpression of TP73-AS1 promoted CRC cell growth, proliferation, migration and invasion in vitro; and knockdown of TP73-AS1 significantly inhibited CRC cell growth, proliferation, migration and invasion in vitro as well as tumor growth in vivo. Bioinformatics analysis and luciferase reporter assay indicated that TP73-AS1 could bind directly with miR-194, and TP73-AS1 negatively regulated the expression of miR-194 in CRC cells. Further study indicated that miR-194 negatively regulated the downstream target of transforming growth factor alpha (TGFα) via targeting its 3' untranslated region, and TP73-AS1 positively regulated the expression of TGFα in CRC cells. Moreover, overexpression of miR-194 suppressed CRC cell proliferation and invasion, and attenuated the effects of TP73-AS1 overexpression on CRC cell proliferation and invasion. Silence of TGFα inhibited CRC cell proliferation and invasion, and also reversed the effects of TP73-AS1 overexpression on CRC cell proliferation and invasion.
CONCLUSIONS: this study demonstrated that TP73-AS1 regulated CRC progression by acting as a competitive endogenous RNA to sponge miR-194 to modulate the expression of TGFα.

Yao Y, Sun Y, Jiang Y, et al.
Enhanced expression of lncRNA TP73-AS1 predicts adverse phenotypes for cholangiocarcinoma and exerts oncogenic properties in vitro and in vivo.
Biomed Pharmacother. 2018; 106:260-266 [PubMed] Related Publications
Cholangiocarcinoma (CCA) is one of the most aggressive malignancies with increasing incidence worldwide. Various evidence documents that abnormally expressed long non-coding RNAs (lncRNAs) play important roles in tumorigenesis and progression. TP73-AS1 is a novel cancer-related lncRNA that contributes to the development of several malignancies. However, its clinical value and potential effects on CCA remains unknown. RT-qPCR was used to measure the expression levels of TP73-AS1 in CCA tissues and paired non-tumor tissues and the association between TP73-AS1 expression and clinicopathological characteristics was analyzed. In addition, the functional roles of TP73-AS1 in CCA were detected both in vitro and in vivo. The results illustrated that TP73-AS1 transcription is enhanced in both CCA tissue samples and cell lines, and this upregulation is closely associated with larger tumor size (p=0.008) and advanced TNM stage (p=0.026) in patients with CCA. For the part of functional assays, silencing of TP73-AS1 could attenuate CCA cell growth both in vitro and in vivo. Additionally, silencing of TP73-AS1 facilitates apoptosis via activating caspase-3 and caspase-9. Importantly, TP73-AS1 expression did not affect HIBEC cell growth and apoptosis. Moreover, TP73-AS1 could also facilitate migration and invasion potential of CCA cells. Collectively, these findings may help to develop a potential therapeutic target for the patients with CCA.

Lei B, Yu L, Jung TA, et al.
Prospective Series of Nine Long Noncoding RNAs Associated with Survival of Patients with Glioblastoma.
J Neurol Surg A Cent Eur Neurosurg. 2018; 79(6):471-478 [PubMed] Related Publications
OBJECTIVE:  To analyze the long noncoding RNA (lncRNA) expression profile of glioblastoma multiforme (GBM) and identify prognosis-related lncRNAs, as well as their related protein-coding genes and functions.
METHOD:  The lncRNA expression profiles were obtained by microarray in six samples each of GBM and normal brain tissue. The lncRNAs expressed were significantly different between the two groups and used to detect their associations with patient survival time by downloading the related data from The Cancer Genome Atlas (TCGA). The total RNA-sequencing data of 152 patients diagnosed GBM level 3 with complete clinic information was downloaded. The survival time-dependent lncRNAs were identified by multivariate Cox regression analysis. For the survival time-dependent lncRNAs, we used the Pearson correlation coefficient and
RESULTS:  More than 1,000 antisense lncRNAs and enhancer lncRNAs were selected for analysis in this study. Data from 152 cases with RNA-seq of GBM level 3 with complete information on GBM were downloaded from the TCGA database. Univariate Cox regression analysis revealed 19 lncRNAs with survival time dependency. These nine lncRNAs were used to construct our survival model via multivariate Cox regression analysis: TP73-AS1, AC078883.3, RP11-944L7.4, HAR1B, RP4-635E18.7, HOTAIR, SAPCD1-AS1, AC104653.1, and RP5-1172N10.2. The nine lncRNAs associated with them were inputted into the DAVID database for gene ontology and KEGG function enrichment analysis. The result showed these genes were enriched with ion binding, transport, cell-cell signaling, plasma membrane parts, and more, and they were mainly related to neuroactive ligand-receptor interaction pathway, calcium signaling pathway, and the mitogen-activated protein kinase signaling pathway.
CONCLUSION:  The nine lncRNAs were a set of biomarkers for the prognosis of patients with GBM, enabling a more accurate prediction of survival and revealing more biological functions.

Molnár B, Galamb O, Péterfia B, et al.
Gene promoter and exon DNA methylation changes in colon cancer development - mRNA expression and tumor mutation alterations.
BMC Cancer. 2018; 18(1):695 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
BACKGROUND: DNA mutations occur randomly and sporadically in growth-related genes, mostly on cytosines. Demethylation of cytosines may lead to genetic instability through spontaneous deamination. Aims were whole genome methylation and targeted mutation analysis of colorectal cancer (CRC)-related genes and mRNA expression analysis of TP53 pathway genes.
METHODS: Long interspersed nuclear element-1 (LINE-1) BS-PCR followed by pyrosequencing was performed for the estimation of global DNA metlyation levels along the colorectal normal-adenoma-carcinoma sequence. Methyl capture sequencing was done on 6 normal adjacent (NAT), 15 adenomatous (AD) and 9 CRC tissues. Overall quantitative methylation analysis, selection of top hyper/hypomethylated genes, methylation analysis on mutation regions and TP53 pathway gene promoters were performed. Mutations of 12 CRC-related genes (APC, BRAF, CTNNB1, EGFR, FBXW7, KRAS, NRAS, MSH6, PIK3CA, SMAD2, SMAD4, TP53) were evaluated. mRNA expression of TP53 pathway genes was also analyzed.
RESULTS: According to the LINE-1 methylation results, overall hypomethylation was observed along the normal-adenoma-carcinoma sequence. Within top50 differential methylated regions (DMRs), in AD-N comparison TP73, NGFR, PDGFRA genes were hypermethylated, FMN1, SLC16A7 genes were hypomethylated. In CRC-N comparison DKK2, SDC2, SOX1 genes showed hypermethylation, while ERBB4, CREB5, CNTN1 genes were hypomethylated. In certain mutation hot spot regions significant DNA methylation alterations were detected. The TP53 gene body was addressed by hypermethylation in adenomas. APC, TP53 and KRAS mutations were found in 30, 15, 21% of adenomas, and in 29, 53, 29% of CRCs, respectively. mRNA expression changes were observed in several TP53 pathway genes showing promoter methylation alterations.
CONCLUSIONS: DNA methylation with consecutive phenotypic effect can be observed in a high number of promoter and gene body regions through CRC development.

Pieraccioli M, Nicolai S, Pitolli C, et al.
ZNF281 inhibits neuronal differentiation and is a prognostic marker for neuroblastoma.
Proc Natl Acad Sci U S A. 2018; 115(28):7356-7361 [PubMed] Article available free on PMC after 01/11/2019 Related Publications
Derangement of cellular differentiation because of mutation or inappropriate expression of specific genes is a common feature in tumors. Here, we show that the expression of ZNF281, a zinc finger factor involved in several cellular processes, decreases during terminal differentiation of murine cortical neurons and in retinoic acid-induced differentiation of neuroblastoma (NB) cells. The ectopic expression of ZNF281 inhibits the neuronal differentiation of murine cortical neurons and NB cells, whereas its silencing causes the opposite effect. Furthermore, TAp73 inhibits the expression of ZNF281 through miR34a. Conversely, MYCN promotes the expression of ZNF281 at least in part by inhibiting miR34a. These findings imply a functional network that includes p73, MYCN, and ZNF281 in NB cells, where ZNF281 acts by negatively affecting neuronal differentiation. Array analysis of NB cells silenced for ZNF281 expression identified GDNF and NRP2 as two transcriptional targets inhibited by ZNF281. Binding of ZNF281 to the promoters of these genes suggests a direct mechanism of repression. Bioinformatic analysis of NB datasets indicates that ZNF281 expression is higher in aggressive, undifferentiated stage 4 than in localized stage 1 tumors supporting a central role of ZNF281 in affecting the differentiation of NB. Furthermore, patients with NB with high expression of ZNF281 have a poor clinical outcome compared with low-expressors. These observations suggest that ZNF281 is a controller of neuronal differentiation that should be evaluated as a prognostic marker in NB.

Yang G, Song R, Wang L, Wu X
Knockdown of long non-coding RNA TP73-AS1 inhibits osteosarcoma cell proliferation and invasion through sponging miR-142.
Biomed Pharmacother. 2018; 103:1238-1245 [PubMed] Related Publications
Long non-coding RNA P73 antisense RNA 1 T (lncRNA TP73-AS1) has been shown to involve in the progression of numerous tumors. Nevertheless, the expression as well as the functional mechanisms of TP73-AS1 in osteosarcoma (OS) are still largely unknown. This study aimed to explore the roles and underlying mechanism of TP73-AS1 in OS progression. In thye present study, TP73-AS1 expression was significantly increased in OS tissues and cell lines. High TP73-AS1 expression was associated with poor overall survival of OS patients. TP73-AS1 knockdown suppressed OS cells proliferation and invasion in vitro as well as tumor growth in vivo. Furthermore, we identified that miR-142 could act as a direct target for TP73-AS1 and miR-142 inhibition reversed the suppression of OS cells proliferation and invasion induced by TP73-AS1 knockdown. In addition, we showed that TP73-AS1 could function as a sponge of miR-142 to positively regulate Rac1 in OS cells. Thus, our data suggested that TP73-AS1 served as an oncogenic lncRNA in OS progression, and could be regarded as an efficient therapeutic target in the treatment of OS.

Jiang H, Cheng L, Hu P, Liu R
MicroRNA‑663b mediates TAM resistance in breast cancer by modulating TP73 expression.
Mol Med Rep. 2018; 18(1):1120-1126 [PubMed] Related Publications
Breast cancer is the second leading cause of cancer‑associated mortalities in women. Tamoxifen (TAM) is an endocrine therapy commonly used in the treatment of patients with breast cancer expressing estrogen receptor α. However, treatment often ends in failure due to the emergence of drug resistance. MicroRNAs (miRNAs), a family of small non‑coding RNAs, serve critical roles in the regulation of gene expression and cell events. To date, whether miRNA‑663b could mediate TAM resistance in breast cancer remains unknown. Therefore, the aim of the present study was to investigate the role of miRNA‑663b in TAM resistance in breast cancer. The results demonstrated that miRNA‑663b was upregulated in breast cancer with TAM resistance. Tumor protein 73 (TP73) was a direct target of miRNA‑663b, and was negatively regulated by miRNA‑663b in MCF‑7 cells. Furthermore, it was identified that downregulation of miRNA‑663b inhibited cell proliferation ability and promoted cell apoptosis, resulting in enhanced TAM sensitivity. In addition, these findings suggested that TP73 silencing may have eliminated the effects of miRNA‑663b inhibitor on breast cancer cells. In conclusion, the present study verified a novel molecular link between miRNA‑663b and TP73, and indicated that miRNA‑663b may be a critical therapeutic target in breast cancer.

Zhang L, Fang F, He X
Long noncoding RNA TP73-AS1 promotes non-small cell lung cancer progression by competitively sponging miR-449a/EZH2.
Biomed Pharmacother. 2018; 104:705-711 [PubMed] Related Publications
Long noncoding RNAs (lncRNAs) are a type of noncoding RNA transcript that are characterized by lack of protein-coding capacity. The vital role of lncRNAs in non-small cell lung cancer (NSCLC) is attracting increasingly more attention. In the present study, we investigate the role of lncRNA antisense RNA of the TP73 gene (TP73-AS1) in NSCLC carcinogenesis. The results demonstrate that TP73-AS1 is markedly upregulated in NSCLC tissues, and functional experiments revealed that TP73-AS1 is significantly increased in NSCLC tissue and cell lines, indicating a possible oncogenic role. In loss-of-function assays, the knockdown of TP73-AS1 inhibited NSCLC cell proliferation, tumor growth and cycle progression in vivo and in vitro. Bioinformatic tools predicted that miR-449a both targeted the 3'-UTR of TP73-AS1 and EZH2, which was confirmed using luciferase reporter assay and AGO2-dependent RNA immunoprecipitate (RIP). TP73-AS1 and miR-449a were in the same RNA-induced silencing complex (RISC). In summary, the results indicate an explicit oncogenic role of TP73-AS1 in the NSCLC tumorigenesis, suggesting a TP73-AS1-miR-449a-EZH2 axis and providing new insight for NSCLC tumorigenesis.

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