Open Access

Attenuated ZHX3 expression is predictive of poor outcome for liver cancer: Indication for personalized therapy

  • Authors:
    • Yanjie You
    • Fangrui Hu
    • Shengjuan Hu
  • View Affiliations

  • Published online on: May 25, 2022     https://doi.org/10.3892/ol.2022.13345
  • Article Number: 224
  • Copyright: © You et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The zinc‑fingers and homeoboxes (ZHX) family members have been characterized as master regulators in cancer initiation and development. The present study performed in silico data‑mining with publicly available datasets and immunohistochemistry to assess the expression status of ZHX factors and the corresponding prognostic implications in liver cancer. Increased ZHX3 mRNA expression was associated with favorable overall survival in patients with liver cancer. Subgroups analyses revealed a significant association between the expression of ZHX factors and outcomes in select patient cohorts. Immunohistochemical analysis supported that ZHX3 expression was an independent prognostic indicator for patient survival. These results suggested that dysregulation of ZHX factors is involved in disease progression and ZHX3 expression may serve as a prognostic biomarker for liver cancer.

Introduction

Primary liver cancer remains one of the commonest types of cancers and hepatocellular carcinoma (HCC) is its major histologic subtype (1). Incidence and mortality of liver cancer are associated with the infection of viral hepatitis, which is a disease with significant geographic distributions worldwide (2). Although multiple novel techniques are now available for treatment of this heterogeneous disease, identification and validation of molecular factors that hold prognostic and therapeutic promise are urgently needed.

Through past efforts in finding novel molecular markers associated with survival outcomes of patients with breast and gastric cancers by in silico data-mining analysis, it was found that the zinc-fingers and homeoboxes (ZHX) family members may be among the targets (3,4). ZHX factors, including ZHX1, ZHX2 and ZHX3, have been reported as a group of transcription factors with two zinc-finger motifs and five homeobox DNA-binding domains existing in the cell nucleus (510). Evidence has indicated that ZHX factors are important transcriptional regulators in downstream signaling that is involved in the osteogenic differentiation of mesenchymal stem cells, development and differentiation of hematopoietic cells and maintenance of neural progenitors (5,11,12). Misexpression of ZHX factors has been associated with development of various diseases, such as neurological, hematological and kidney diseases (5,13,14). Moreover, results from relevant studies suggest that ZHX family members are involved in initiation and development of a variety of types of cancer (35). The crucial roles of ZHX factors provide reason enough for them as candidate biomarkers for cancer surveillance, diagnosis and survival prediction. Nevertheless, to the best of the authors' knowledge, the prognostic values of individual ZHX factors in liver cancer remain to be elucidated. The present study examined the expression patterns of ZHX factors and the corresponding prognostic implications in liver cancer, using integrative bioinformatics analyses with a set of online available databases, including the Oncomine (http://www.oncomine.org/) (15), Tumor IMmune Estimation Resource (TIMER) 2.0 (16), Cancer Cell Line Encyclopedia (CCLE) database (http://sites.broadinstitute.org/ccle//) (3,4,17), Kaplan-Meier Plotter (http://kmplot.com/analysis/) (18,19) and cBioPortal (http://www.cbioportal.org/) (20,21). Further, immunohistochemistry was performed to confirm ZHX3 protein expression in liver cancer, as well as its association with clinicopathologic variables and survival outcomes.

Materials and methods

Oncomine database analysis

The present study analyzed the expression of distinct ZHX factors in cancers through the Oncomine database (15). When the transcriptional expression of ZHX factors in tumor tissues were compared to those in noncancerous tissues, P<0.01 with a fold-change = 2 was considered as statistically significant. Paired Student's t-test was used.

Tumor IMmune Estimation Resource (TIMER) database analysis

TIMER web server is an integrated online database for comprehensive analysis of immune infiltrates through multiple types of cancer (16). In the current study, the gene expression profile of ZHX factors in multiple types of cancer were evaluated via TIMER database analysis (https://cistrome.shinyapps.io/timer/).

CCLE database analysis

The mRNA expression levels of specific ZHX factors in diverse types of cancer cell lines were determined using the CCLE database (http://portals.broadinstitute.org/ccle/), as described previously (3,4,17).

Kaplan-Meier Plotter survival analysis

The prognostic impacts of ZHX mRNA levels were analyzed using the Kaplan-Meier Plotter online database, which includes the information of 54,675 genes on survival using 10,461 clinical cancer samples, including 364 from patients with liver cancer for outcome prediction analysis (18,19). Data sources contain those from the Gene Expression Omnibus (GEO), the European Genome-phenome Archive (EGA) and the Cancer Genome Atlas (TCGA). To investigate the overall survival (OS) and relapse-free survival (RFS) rates, patients were separated into high and low-expression groups according to the median mRNA expression levels so that survival analyses were conducted to produce Kaplan-Meier plots. Hazard ratio with 95% confidence interval and log-rank P-values were calculated.

cBioPortal cancer genomics database analysis

The effects of genomic alterations of ZHX genes containing mutations and copy-number variance on OS and disease-free survival (DFS) rates in patients with liver cancer were analyzed using the cBioPortal online database (20,21). The raw data used prior to bioinformatic analysis are derived from GEO and TCGA. In the present study, OncoPrint in cBioPortal were employed to demonstrate the proportion and distribution of samples with genetic alterations in ZHX genes.

Immunohistochemistry and evaluation

The immunohistochemical staining for ZHX3 protein expression was performed using a standard EnVision complex method previously described (3,4,22,23). One tissue microarray chip containing 94 primary HCC tissues and 86 adjacent noncancerous tissues was purchased from Outdo Biotech Co., Ltd. Following deparaffinization, rehydration and antigen retrieval, 4-µm sections of tissue samples were incubated with a rabbit polyclonal anti-ZHX3 antibody (catalog no. ab84677; dilution, 1:500; Abcam) overnight at 4°C. ZHX3 protein staining was visualized using an EnVision antibody complex (anti-Mouse/Rabbit) method with an Envision Detection kit (OriGene Technologies, Inc.) and 3,3′-diaminobenzidine as the chromogen substrate. Nuclei were counterstained with 0.5% hematoxylin for 2 min at room temperature.

A total of 10 random microscopic fields per slide (magnification, ×400) were evaluated by two independent observers who were unaware of the clinical information. Immunostaining was graded semi-quantitatively by multiplication of staining intensity and percentage of positive cells. The mean percentage of positively stained cells was scored as follows: 0–5% (0); 5–25% (1); 26–50% (2); 51–75% (3); and 76–100% (4). The staining intensity was categorized as follows: Absent (0); weak (1); moderate (2); and strong (3). Tumor samples exhibiting a final staining score of <2 were defined as low ZHX3 expression and those with scores ≥2 as high ZHX3 expression.

Statistical analysis

Statistical analyses were conducted using the SPSS 17.0 statistical software package (SPSS Inc.). Associations between the expression levels of ZHX factors and clinicopathological variables were assessed using the Pearson's χ2 test or Fisher's exact test. Survival curves were produced using the Kaplan-Meier method and compared with the log-rank test. The prognostic significance of the clinicopathological variables was determined using a univariate Cox regression analysis. A Cox proportional hazards regression model for multivariate analysis was employed for factors that achieved significance in the univariate analysis. P<0.05 was considered to indicate a statistically significant difference.

Results

mRNA expression profile of ZHX factors in human cancers

Hitherto, three ZHX factors were characterized in a variety of types of human cancer. Our previous study revealed that the Oncomine database provided a total of 308, 434 and 416 unique analyses for ZHX1, ZHX2 and ZHX3, respectively (3). However, the mRNA levels of ZHX factors were not found in liver cancer datasets. The present study thus examined the mRNA expression of ZHX factors in multiple types of cancer using the TIMER online database. The expression of all three ZHX factors was significantly higher in liver hepatocellular carcinoma (LIHC) tissues than in normal tissues (Fig. 1). Additionally, analyses from the CCLE database revealed that the mRNA levels of ZHX1, ZHX2 and ZHX3 in liver cancer cells ranked the 27th, 11th and 23rd highest across all types of cancer, respectively (Fig. 2).

Association between the expression of ZHX factors and survival outcomes

The present study next identified the prognostic impacts of ZHX family members on patient outcome via Kaplan-Meier plotter survival analysis. ZHX1 mRNA level was not significantly associated with OS in patients with liver cancer (Fig. 3A). Subgroup analyses showed no significant association between ZHX1 mRNA expression and male patients or female patients (Fig. 3B and C). Similarly, ZHX1 mRNA expression was not correlated with RFS in patients with liver cancer. Low expression of ZHX1 predicted a longer RFS rate in male patients, but not in female patients (Fig. 3E and F). Increased ZHX1 expression also displayed a longer RFS rate in patients without hepatitis virus infection (Fig. 3G and H).

No significant association was observed between ZHX2 mRNA levels and OS in patients with liver cancer (Fig. 4A). Subgroup analyses suggested that decreased ZHX2 expression indicated a longer OS rate in patients with stage III/IV tumors but not in patients with stage I/II tumors (Fig. 4B and C). Decreased ZHX2 mRNA level was associated with an improved OS in patients without hepatitis virus infection (Fig. 4D), whereas increased ZHX2 expression was associated a favorable OS in patients with hepatitis virus infection (Fig. 4E). Similarly, ZHX2 expression was not significantly associated with RFS in patients with liver cancer (Fig. 4F). High expression of ZHX2 implied longer RFS times in patients with micro vascular invasion, but not in those without vascular invasion (Fig. 3G and H).

Regarding ZHX3, its upregulation was found to be associated with a prolonged OS rate in patients with liver cancer (Fig. 5A). Subgroup analyses showed that no significant correlation between ZHX2 expression and OS either in male patients or in female patients (Fig. 5B and C). Increased ZHX3 expression exhibited longer OS times in patients with Stage I/II tumors and Stage III/IV tumors (Fig. 5D and E). High ZHX3 mRNA level represented an improved OS rate in patients with micro vascular invasion, but not in those without micro vascular invasion (Fig. 5F and G). In addition, elevated ZHX3 expression illustrated a longer OS in patients without hepatitis virus infection (Fig. 5H), but not in those with hepatitis virus infection (Fig. 5I).

Correlation between genetic alterations of ZHX factors and survival outcomes

The prognostic association between genetic alterations of ZHX factors and outcomes in patients with liver cancer was further characterized using the CbioPORTAL online database. The genetic alteration rates for ZHX1, ZHX 2 and ZHX3 were 10, 10 and 0.6%, respectively (Fig. 3). The genetic alteration of ZHX2 was found to be associated with OS in patient with liver cancer (Fig. 6C). Nevertheless, no other significant relationship was observed between genetic alterations of ZHX factors and patient survival, as regarding either OS or DFS (Fig. 6B and D-G).

ZHX3 expression is an independent prognostic factor in liver cancer

To support the above results, the expression status of ZHX3 protein was thus examined using one tissue microarray chip containing total 94 primary HCC specimens. A high level of ZHX3 protein expression primarily in the cytoplasm of cancer cells in 48.9% (46/94) of the HCC specimens tested was observed (Fig. 7). Low ZHX3 expression was found to be associated with larger tumor size, advanced TNM staging and T stage, positive thrombus status and TP53 expression (Table I). Kaplan-Meier survival analyses demonstrated that patients with high ZHX3 expression had an improved OS compared with those with low ZHX3 expression (Fig. 8A). Subgroup analyses showed that high ZHX3 expression indicated an improved OS in patients both with T1/T2 tumors and T3/T4 tumors (Fig. 8B and C). ZHX3 overexpression also exhibited a longer OS in patients both with Stage I/II and Stage III/IV tumors (Fig. 8D and E). In addition, elevated ZHX3 suggested an improved OS in patients with histological grade I/II tumors (Fig. 8F). In the univariate analysis, larger tumor size, advanced TNM stage, higher histological grade, positive thrombus status and ZHX3 expression were determined to be associated with an unfavorable OS (Table II). After correcting the prognostic variables obtained in the univariate analysis, only histological grade and ZHX3 expression kept the independent implication in the multivariate analysis (Table II).

Table I.

Correlation between ZHX3 expression and clinicopathological variables in liver cancer.

Table I.

Correlation between ZHX3 expression and clinicopathological variables in liver cancer.

ZHX3 expression

ParametersNo. of patientsLow, n (%)High, n (%)P-value
Age
  ≤60 years5329 (54.7)24 (45.3)0.491
  >60 years4019 (47.5)21 (52.5)
  NA1
Sex
  Male103 (30.0)7 (70.0)0.194
  Female8445 (53.6)39 (46.4)
Tumor size
  ≤5 cm399 (23.1)30 (76.9)<0.001
  >5 cm5438 (70.4)16 (29.6)
  NA1
Histological grade
  I/II6627 (40.9)39 (59.1)0.932
  III2821 (75.0)7 (25.0)
TNM Stage
  I/II438 (18.6)35 (81.4)<0.001
  III/IV4337 (86.0)6 (14.0)
  NA8
T Stage
  T1/T2438 (18.6)35 (81.4)<0.001
  T3/T44337 (86.0)6 (14.0)
  NA8
Thrombus
  Negative7536 (48.0)39 (52.0)0.013
  Positive77 (100.0)0 (0.0)
  NA12
Cirrhosis
  Negative5831 (53.4)27 (46.6)0.557
  Positive3617 (47.2)19 (52.8)
AFP
  Negative3923 (59.0)26(41.0)0.167
  Positive5424 (44.4)30(55.6)
  NA1
CD34
  Negative3717 (45.9)20 (54.1)0.524
  Positive5529 (52.7)26 (47.3)
  NA1
Ki67
  Negative4419 (43.2)25 (56.8)0.179
  Positive4928 (57.1)21 (42.9)
  NA1
TP53
  Negative4417 (38.6)27 (61.4)0.030
  Positive4930 (61.2)19 (28.8)
PDL-1
  Negative4322 (51.2)21 (48.8)0.911
  Positive4222 (52.4)20 (47.6)
  NA9
CD8
  Negative4220 (47.6)22 (52.4)0.528
  Positive4625 (54.3)21 (45.6)
  NA6

[i] NA, not available; ZHX, zinc-fingers and homeoboxes; AFP, α-fetoprotein; PDL-1, programmed death-ligand 1.

Table II.

Univariate and multivariate analyses of the factors correlated with overall survival of liver carcinoma patients.

Table II.

Univariate and multivariate analyses of the factors correlated with overall survival of liver carcinoma patients.

Univariate analysisMultivariate analysis


VariablesHR (95% CI)P-valueHR (95% CI)P-value
Tumor size
  >5 cm vs. ≤5 cm2.397 (1.365-4.210)0.0021.002 (0.445-2.256)0.996
TNM Stage
  III/IV vs. I/II2.860 (1.611-5.077)<0.0010.824 (0.321-2.115)0.687
Histological grade
  III/IV vs. I/II3.401 (2.002-5.779)<0.0012.067 (1.07-3.995)0.031
Thrombus
  Positive vs. Negative2.644 (1.117-6.259)0.0271.732 (0.580-5.170)0.325
ZHX3 expression
  Low vs. high0.179 (0.098-0.329)<0.0010.173 (0.066-0.453)<0.001

[i] HR, hazard ratio; CI, confidence interval; ZHX, zinc-fingers and homeoboxes.

Discussion

The present study is part of a continuing effort to explore molecular targets of liver cancer behaviors with reliability to predict outcome and promise as targets for directed therapy. Identification of this issue may be important to improve clinical management of liver cancer in the future. Consequently, the results of the present study using data-mining analyses as well as immunohistochemistry provided an in-depth investigation into the prognostic values of ZHX family members in patients with liver cancer.

ZHX1 has been identified as a tumor suppressor in several types of cancer (2428). On the contrary, two reports show that ZHX1 might act as an oncogene in cholangiocarcinoma and glioblastoma (29,30). To the best of the authors' knowledge, except for our two reports (3,4), no other study has unraveled the association between ZHX1 expression and outcomes of patients with cancer. Of note, its prognostic impact on different cancers appears to be contradictory. The present authors previously reported that high ZHX1 expression predicts worse OS for breast cancer but present better OS for gastric cancer, suggesting its diverse roles in development of different types of cancer (3,4). It was inferred that different sample sources, histological types and intrinsic differences in each type of cancers may be possible to explain this disparity. Although there no relevance was found between ZHX1 expression and OS in patients with liver cancer in the present study, a prognostic value for ZHX1 was identified in subgroup analyses, i.e., a significant association between low ZHX1 mRNA levels and longer RFS in male patients as well as in patient without hepatitis virus infection.

Several studies have reported tumor-suppressor roles of ZHX2 in multiple types of cancer, including liver cancer (3138). However, no significant association was observed between ZHX2 expression and OS or RFS in patients with liver cancer. Decreased ZHX2 expression was only observed to be correlated with an improved OS in patients with Stage III/IV tumors or an improved RFS in patients with micro vascular invasion. Dysregulation of ZHX2 has been described to function in the transcriptional inhibition of cancer markers in normal hepatocytes (31). It has been noted that gene promoter methylation-medicated silencing of ZHX2 frequent occurs in HCC and overexpression of ZHX2 suppresses proliferation and augments the chemo-sensitivity of HCC cells (3235). It has been also reported that HBV inhibits ZHX2 expression and accelerates the proliferation of HCC cells through the activation of miR-155 and, conversely, ZHX2 represses HBV replication through epigenetic and non-epigenetic manners (35,36). These observations seem consistent with the findings of the present study, i.e., ZHX2 expression predicted better OS in patients with hepatitis infection, suggesting that ZHX2 may exert different functions according the different microenvironment during development of liver cancer.

Consistent with our previous study in breast cancer (3), attenuated ZHX3 expression was observed to be correlated with unfavorable OS in patients with liver cancer. The data also demonstrated that elevated ZHX3 was associated with an improved OS in patients with both Stage I/II and Stage III/IV tumors, suggesting that ZHX3 might be valuable in predicting the outcomes of patients with early-stage malignancy. This conclusion is contrary to the oncogene function of ZHX3 in gastric cancer in another study (4). To support the observation by in silico analyses, protein expression of ZHX3 was also examined by immunohistochemistry in cancer tissues. The data of the present study characterized that decreased ZHX3 levels were significantly associated with malignant properties and suggested that ZHX3 expression is an independent prognostic factor in liver cancer. Notably, the genetic alteration rate of ZHX3 was lower than that of ZHX1 and ZHX2 in liver cancer, which is similar to our previous studies in breast and gastric cancers (3,4). This lower frequency of ZHX3 gene alteration in the types of cancer that we observed suggest that ZHX3 may exert more important biological functions as an tumor suppressor gene.

In summary, the present study systematically examined the expression pattern of ZHX factors and the corresponding prognostic significance in liver cancer, based on in silico analysis and immunohistochemistry analyses. The results suggested that ZHX family members are distinct prognostic biomarkers for this disease. Future research should be performed to discover the exact functions of ZHX family members in liver cancer, which may support that ZHX factors could serve as prognostic predicators and promising therapeutic targets for precision medicine.

Acknowledgements

Not applicable.

Funding

This work was supported by the Natural Science Foundation of Ningxia Hui Autonomous Region, China (grant no. 2021AAC03318) and in part by the National Natural Science Foundation of China (grant no. 81860426).

Availability of data and materials

The dataset used and/or analyzed in the current study is available from the corresponding authors on reasonable request.

Authors' contributions

YY, FH and SH conceived the study, designed and performed the experiments, analyzed and interpret the data and drafted the manuscript. YY and SH confirm the authenticity of all raw data. All authors read and approved the final manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy and integrity of any part of the work are appropriately investigated and resolved.

Ethics approval and consent to participate

The study protocol conformed to the ethical guidelines outlined in the Declaration of Helsinki and was approved by the Institutional Review Board (approval no. 07-170) of Ningxia Hui Autonomous Region People's Hospital.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Yu J, Tao Q, Cheung KF, Jin H, Poon FF, Wang X, Li H, Cheng YY, Röcken C, Ebert MP, et al: Epigenetic identification of ubiquitin carboxyl-terminal hydrolase L1 as a functional tumor suppressor and biomarker for hepatocellular carcinoma and other digestive tumors. Hepatology. 48:508–518. 2008. View Article : Google Scholar : PubMed/NCBI

3 

You Y, Ma Y, Wang Q, Ye Z, Deng Y and Bai F: Attenuated ZHX3 expression serves as a potential biomarker that predicts poor clinical outcomes in breast cancer patients. Cancer Manag Res. 11:1199–1210. 2019. View Article : Google Scholar : PubMed/NCBI

4 

You Y, Bai F, Li H, Ma Y, Yao L, Hu J and Tian Y: Prognostic value and therapeutic implications of ZHX family member expression in human gastric cancer. Am J Transl Res. 12:3376–3388. 2020.PubMed/NCBI

5 

Liu Y, Ma D and Ji C: Zinc fingers and homeoboxes family in human diseases. Cancer Gene Ther. 22:223–226. 2015. View Article : Google Scholar : PubMed/NCBI

6 

Barthelemy I, Carramolino L, Gutiérrez J, Barbero JL, Márquez G and Zaballos A: A novel mouse homeodomain protein containing two zinc-fingers and five homeodomains. Biochem Biophys Res Commun. 224:870–876. 1996. View Article : Google Scholar : PubMed/NCBI

7 

Hirano S, Yamada K, Kawata H, Shou Z, Mizutani T, Yazawa T, Kajitani T, Sekiguchi T, Yoshino M, Shigematsu Y, et al: Rat zinc-fingers and homeoboxes 1 (ZHX1), a nuclear factor-YA-interacting nuclear protein, forms a homodimer. Gene. 290:107–114. 2002. View Article : Google Scholar : PubMed/NCBI

8 

Kawata H, Yamada K, Shou Z, Mizutani T, Yazawa T, Yoshino M, Sekiguchi T, Kajitani T and Miyamoto K: Zinc-fingers and homeoboxes (ZHX) 2, a novel member of the ZHX family, functions as a transcriptional repressor. Biochem J. 373:747–757. 2003. View Article : Google Scholar : PubMed/NCBI

9 

Yamada K, Kawata H, Shou Z, Hirano S, Mizutani T, Yazawa T, Sekiguchi T, Yoshino M, Kajitani T and Miyamoto K: Analysis of zinc-fingers and homeoboxes (ZHX)-1-interacting proteins: Molecular cloning and characterization of a member of the ZHX family, ZHX3. Biochem J. 373:167–178. 2003. View Article : Google Scholar : PubMed/NCBI

10 

Kawata H, Yamada K, Shou Z, Mizutani T and Miyamoto K: The mouse zinc-fingers and homeoboxes (ZHX) family; ZHX2 forms a heterodimer with ZHX3. Gene. 323:133–140. 2003. View Article : Google Scholar : PubMed/NCBI

11 

Suehiro F, Nishimura M, Kawamoto T, Kanawa M, Yoshizawa Y, Murata H and Kato Y: Impact of zinc fingers and homeoboxes 3 on the regulation of mesenchymal stem cell osteogenic differentiation. Stem Cells Dev. 20:1539–1547. 2011. View Article : Google Scholar : PubMed/NCBI

12 

Liu G, Clement LC, Kanwar YS, Avila-Casado C and Chugh SS: ZHX proteins regulate podocyte gene expression during the development of nephrotic syndrome. J Biol Chem. 281:39681–39692. 2006. View Article : Google Scholar : PubMed/NCBI

13 

Clement LC, Liu G, Perez-Torres I, Kanwar YS, Avila-Casado C and Chugh SS: Early changes in gene expression that influence the course of primary glomerular disease. Kidney Int. 72:337–347. 2007. View Article : Google Scholar : PubMed/NCBI

14 

Nagel S, Ehrentraut S, Meyer C, Kaufmann M, Drexler HG and MacLeod RA: Aberrantly expressed OTX homeobox genes deregulate B-cell differentiation in hodgkin lymphoma. PLoS One. 10:e01384162015. View Article : Google Scholar : PubMed/NCBI

15 

Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A and Chinnaiyan AM: ONCOMINE: A cancer microarray database and integrated data-mining platform. Neoplasia. 6:1–6. 2004. View Article : Google Scholar : PubMed/NCBI

16 

Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, Li B and Liu XS: TIMER: A web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res. 77:e108–e110. 2017. View Article : Google Scholar : PubMed/NCBI

17 

Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, Wilson CJ, Lehár J, Kryukov GV, Sonkin D, et al: The cancer cell line encyclopedia enables predictive modelling of anticancerdrug sensitivity. Nature. 483:603–607. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Lanczky A, Nagy A, Bottai G, Munkacsy G, Szabo A, Santarpia L and Gyorffy B: miRpower: A web-tool to validate survival-associated miRNAs utilizing expression data from 2,178 breast cancer patients. Breast Cancer Res Treat. 160:439–446. 2016. View Article : Google Scholar : PubMed/NCBI

19 

Szász AM, Lánczky A, Nagy Á, Förster S, Hark K, Green JE, Boussioutas A, Busuttil R, Szabó A and Győrffy B: Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1,065 patients. Oncotarget. 7:49322–49333. 2016. View Article : Google Scholar : PubMed/NCBI

20 

Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, et al: Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 6:pl12013. View Article : Google Scholar : PubMed/NCBI

21 

Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, et al: The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2:401–404. 2012. View Article : Google Scholar : PubMed/NCBI

22 

You Y, Li H, Qin X, Zhang Y, Song W, Ran Y and Gao F: Decreased CDK10 expression correlates with lymph node metastasis and predicts poor outcome in breast cancer patients - a short report. Cell Oncol (Dordr). 38:485–491. 2015. View Article : Google Scholar : PubMed/NCBI

23 

You Y, Li H, Qin X, Ran Y and Wang F.: Down-regulated ECRG4 expression in breast cancer and its correlation with tumor progression and poor prognosis-A short report. Cell Oncol (Dordr). 39:89–95. 2016. View Article : Google Scholar : PubMed/NCBI

24 

Wang J, Liu D, Liang X, Gao L, Yue X, Yang Y, Ma C and Liu J: Construction of a recombinant eukaryotic human ZHX1 gene expression plasmid and the role of ZHX1 in hepatocellular carcinoma. Mol Med Rep. 8:1531–1536. 2013. View Article : Google Scholar : PubMed/NCBI

25 

Wang Z, Ma X, Cai Q, Wang X, Yu B, Cai Q, liu B, Zhu Z and Li C: MiR-199a-3p promotes gastric cancer progression by targeting ZHX1. FEBS Lett. 588:4504–4512. 2014. View Article : Google Scholar : PubMed/NCBI

26 

Ma X, Huang M, Wang Z, Liu B, Zhu Z and Li C: ZHX1 inhibits gastric cancer cell growth through inducing cell-cycle arrest and apoptosis. J Cancer. 7:60–68. 2016. View Article : Google Scholar : PubMed/NCBI

27 

Kwon RJ, Kim YH, Jeong DC, Han ME, Kim JY, Liu L, Jung JS and Oh SO: Expression and prognostic significance of zinc fingers and homeoboxes family members in renal cell carcinoma. PLoS One. 12:e01710362017. View Article : Google Scholar : PubMed/NCBI

28 

Guan J, Liu Z, Xiao M, Hao F, Wang C, Chen Y, Lu Y and Liang J: MicroRNA-199a-3p inhibits tumorigenesis of hepatocellular carcinoma cells by targeting ZHX1/PUMA signal. Am J Transl Res. 9:2457–2465. 2017.PubMed/NCBI

29 

Kwon RJ, Han ME, Kim JY, Liu L, Kim YH, Jung JS and Oh SO: ZHX1 promotes the proliferation, migration and invasion of cholangiocarcinoma cells. PLoS One. 11:e01655162016. View Article : Google Scholar : PubMed/NCBI

30 

Kwon RJ, Han ME, Kim YJ, Kim YH, Kim JY, Liu L, Heo W and Oh SO: Roles of zinc-fingers and homeoboxes 1 during the proliferation, migration, and invasion of glioblastoma cells. Tumour Biol. 39:10104283176945752017. View Article : Google Scholar : PubMed/NCBI

31 

Yamada K, Ogata-Kawata H, Matsuura K, Kagawa N, Takagi K, Asano K, Haneishi A and Miyamoto K: ZHX2 and ZHX3 repress cancer markers in normal hepatocytes. Front Biosci (Landmark Ed). 14:3724–3732. 2009. View Article : Google Scholar : PubMed/NCBI

32 

Lv Z, Zhang M, Bi J, Xu F, Hu S and Wen J: Promoter hypermethylation of a novel gene, ZHX2, in hepatocellular carcinoma. Am J Clin Pathol. 125:740–746. 2006. View Article : Google Scholar : PubMed/NCBI

33 

Yue X, Zhang Z, Liang X, Gao L, Zhang X, Zhao D, Liu X, Ma H, Guo M, Spear BT, et al: Zinc fingers and homeoboxes 2 inhibits hepatocellular carcinoma cell proliferation and represses expression of cyclins A and E. Gastroenterology. 142:1559–1570.e2. 2012. View Article : Google Scholar : PubMed/NCBI

34 

Luan F, Liu P, Ma H, Yue X, Liu J, Gao L, Liang X and Ma C: Reduced nucleic ZHX2 involves in oncogenic activation of glypican 3 in human hepatocellular carcinoma. Int J Biochem Cell Biol. 55:129–135. 2014. View Article : Google Scholar : PubMed/NCBI

35 

Song X, Tan S, Wu Z, Xu L, Wang Z, Xu Y, Wang T, Gao C, Gong Y, Liang X, et al: HBV suppresses ZHX2 expression to promote proliferation of HCC through miR-155 activation. Int J Cancer. 143:3120–3130. 2018. View Article : Google Scholar : PubMed/NCBI

36 

Xu L, Wu Z, Tan S, Wang Z, Lin Q, Li X, Song X, Liu Y, Song Y, Zhang J, et al: Tumor suppressor ZHX2 restricts hepatitis B virus replication via epigenetic and non-epigenetic manners. Antiviral Res. 153:114–123. 2018. View Article : Google Scholar : PubMed/NCBI

37 

Hu S, Zhang M, Lv Z, Bi J, Dong Y and Wen J: Expression of zinc-fingers and homeoboxes 2 in hepatocellular carcinogenesis: A tissue microarray and clinicopathological analysis. Neoplasma. 54:207–211. 2007.PubMed/NCBI

38 

Armellini A, Sarasquete ME, García-Sanz R, Chillón MC, Balanzategui A, Alcoceba M, Fuertes M, López R, Hernández JM, Fernández-Calvo J, et al: Low expression of ZHX2, but not RCBTB2 or RAN, is associated with poor outcome in multiple myeloma. Br J Haematol. 141:212–215. 2008. View Article : Google Scholar : PubMed/NCBI

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July-2022
Volume 24 Issue 1

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Spandidos Publications style
You Y, Hu F and Hu S: Attenuated ZHX3 expression is predictive of poor outcome for liver cancer: Indication for personalized therapy. Oncol Lett 24: 224, 2022
APA
You, Y., Hu, F., & Hu, S. (2022). Attenuated ZHX3 expression is predictive of poor outcome for liver cancer: Indication for personalized therapy. Oncology Letters, 24, 224. https://doi.org/10.3892/ol.2022.13345
MLA
You, Y., Hu, F., Hu, S."Attenuated ZHX3 expression is predictive of poor outcome for liver cancer: Indication for personalized therapy". Oncology Letters 24.1 (2022): 224.
Chicago
You, Y., Hu, F., Hu, S."Attenuated ZHX3 expression is predictive of poor outcome for liver cancer: Indication for personalized therapy". Oncology Letters 24, no. 1 (2022): 224. https://doi.org/10.3892/ol.2022.13345