|Year : 2022 | Volume
| Issue : 3 | Page : 589-597
|Expression of HnRNP A1, ZEB1, and E-cadherin in Hepatocellular carcinoma and their impact on patients' prognosis and survival
Nehal S Abouhashem1, Amira Elwan2, Ahmed S El Hefnawy3, Hanaa A Atwa1
1 Department of Pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2 Department of Clinical Oncology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
3 Department of Surgery, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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|Date of Submission||07-Oct-2021|
|Date of Decision||18-Mar-2022|
|Date of Acceptance||19-Mar-2022|
|Date of Web Publication||21-Jul-2022|
| Abstract|| |
Background: Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies in Egypt. HCCs usually have a poor prognosis because of late diagnosis, aggressive metastasis, and early invasion. Heterogeneous ribonucleoproteins (HnRNPs) are nuclear proteins that play a variety of roles in telomere formation, DNA repair, cell signaling, and gene regulation. Zincfinger Eboxbinding homeoboxes (ZEBs) are transcription factors that have a consistent inverse correlation with Ecadherin in numerous types of cancer and associated with poor prognosis. Aim: This study aimed to verify the prognostic expression of HnRNP A1, ZEB1, and E-cadherin in HCC. Settings and Design: The retrospective study consisted of 54 formalin-fixed paraffin-embedded tissue blocks of hepatocellular carcinoma. Methods and Material: Immunohistochemical staining was performed using antibodies against HnRNP A1, ZEB1, and E-cadherin. The patients were followed at the Clinical Oncology Department from May 2018 to July 2021. Statistical Analysis: SPSS version 20 using the Chi-square test to compare data and the Kaplan–Meier plot for comparing survival. Results: HnRNP A1 high positivity was detected in 59.3% of the cases, whereas negative E-cadherin and ZEB 1 expression presented in 37% and 70.4% of the patients, respectively. A statistically significant relation was present between HnRNP A1, ZEB1, E-cadherin, and various clinicopathological variables. The mean progression-free survival and overall survival in low HnRNP A1 and negative ZEB1 expressions were longer than those exhibited in high HnRNP A1 and positive ZEB1 expressions. Conclusion: HnRNP A1 and ZEB1 expressions are poor prognostic factors of HCC. E-cadherin has an important role in the development of differentiated HCCs and favorable outcome.
Keywords: Hepatocellular carcinoma, HnRNP A1, ZEB1, and E-cadherin
|How to cite this article:|
Abouhashem NS, Elwan A, El Hefnawy AS, Atwa HA. Expression of HnRNP A1, ZEB1, and E-cadherin in Hepatocellular carcinoma and their impact on patients' prognosis and survival. Indian J Pathol Microbiol 2022;65:589-97
|How to cite this URL:|
Abouhashem NS, Elwan A, El Hefnawy AS, Atwa HA. Expression of HnRNP A1, ZEB1, and E-cadherin in Hepatocellular carcinoma and their impact on patients' prognosis and survival. Indian J Pathol Microbiol [serial online] 2022 [cited 2022 Aug 15];65:589-97. Available from: https://www.ijpmonline.org/text.asp?2022/65/3/589/351626
| Introduction|| |
Hepatocellular carcinoma (HCC) is considered one of the most common cancers in the world. HCC is regarded one of the most prevalent malignancies in Egypt, according to the National Institute of Cancer, because of the high incidence of hepatitis B and C infections, which account for around 45.3 percent of all new occurrences of this form of cancer.
HCCs usually have a poor prognosis because of late diagnosis, aggressive metastasis, early invasion, and the lack of effective therapy options. New biomarkers are being needed for anticipating the development of this tumor.
Heterogeneous ribonucleoproteins (HnRNPs) are a family of nuclear proteins that play a variety of roles in telomere formation, DNA repair, cell signaling, and gene regulation at both the transcriptional and translational levels. HnRNP A1 belongs to the A/B subfamily of ubiquitously expressed HnRNPs with diverse activities. It is important in telomere biogenesis; HnRNP A1-deficient cell lines have shorter telomeres than normal HnRNP A1-expressing cell lines.
Moreover, HnRNP A1 is engaged in protein–protein interactions and interacts with the inhibitory subunit of NF-B alpha via its N-terminal RNA-binding domain, leading to activation of nuclear factor B (NF-B). Overexpression of HnRNP A1 has been observed in many tumors such as breast, lung, and colon cancers. Regarding HCC, Zhou et al. reported that HCC patients with high hnRNP A1 expression had poorer prognosis as estimated by shorter OS and higher cumulative recurrence.
Zinc-finger Ebox-binding homeoboxes (ZEBs) are transcription factors. The ZEB family (consisting of ZEB1 and ZEB2) has a consistent inverse correlation with E-cadherin and vimentin in numerous types of cancer. Several studies revealed that abnormal expression of ZEB1 in endometrial, colorectal, and prostate cancers has been linked to disease aggressiveness, low differentiation, metastasis, and poor prognosis. ZEB1 has been shown to regulate E-cadherin expression via interacting with the E-box element inside the proximal region of the promoter. In the literature, Qin et al. concluded that ZEB1 expression is closely linked to carcinogenesis and that it may be a biomarker for the malignant phenotype of HCC, which could be useful in tumor progression monitoring, therapy evaluation, and prognosis prediction.
E-cadherin is an important member of the family of cellular adhesion molecules expressed by epithelial cells. The expression of adhesion molecules, such as cadherin, responsible for tumor invasion and metastasis represents important prognostic predictive markers in patients with HCC.
In this study, we aimed to study the immunohistochemical expression of of HnRNP A1, ZEB1, and E-cadherin in HCC among Egyptian patients and correlate their expression with patients' survival and response to treatment.
| Material and Method|| |
In this study, we have included sections from formalin-fixed paraffin-embedded tissue blocks that were collected from samples of 54 cases of conventional hepatocellular carcinoma (core biopsies and resection biopsy). All cases were retrieved from the Pathology Department, Faculty of Medicine, Zagazig University, and approved by the Ethical Committee (IRB# 8082). The clinical data, pathology reports, and hematoxylin and eosin (H&E)-stained slides for the cases were reviewed to confirm the diagnosis. The histologic grade of HCC was established using the World Health Organization criteria.
The patients were followed at the Clinical Oncology Department; all data were collected with regard to full history, clinical examination, and radiological and lab profile assessment initially and after treatment proposal. Treatment and survival outcomes were analyzed and investigated according to marker expressions from May 2018 to July 2021.
Using antibodies against HnRNP A1 (rabbit monoclonal [EPR12768], dilution 1/200, Abcam, positive control breast carcinoma), ZEB1 (rabbit monoclonal ab EPR17375, dilution1/100, Abcam, positive control, breast carcinoma), and E-cadherin (rabbit monoclonal antibody [ab1416], dilution 1/100, Abcam, positive control breast carcinoma).
Interpretation and evaluation of immunostaining
With regard to HnRNP A1, the percentage of stained cells was graded as 0 (0–5%), 1 (5–25%), 2 (25–50%), and 3 (50–100%), and the intensity of staining was graded as 0 (no staining), 1 (weak), 2 (medium), and 3 (strong) (strong). By calculating the percentage scores with the staining intensity scores, the expression of HnRNP A1 in each sample was estimated. The samples were then categorized as high (≥6) or low (<6) expressing.
Concerning ZEB1 immunostaining, nuclear immunoreactivity for ZEB1 was scored by assessing the number of positive tumor cells as follows: absent (0%), 1–5%, 6–10%, and >10%. The expression of ZEB1 was defined as positive if more than 1% of HCC cells exhibited nuclear staining.
With regard to E-cadherine, it was assessed according to the percentage of positive cells, and the reactivity score was classified as follows: 0 – between 0 and 5% positive cells, +1 – between 5 and 25% positive cells, +2 – between 26 and 50% positive cells, +3 – between 51 and 75% positive cells, and +4 – between 76 and 100% positive cells. The intensity score was scored as mild, moderate, and intense reaction. We considered positive expression as uniform membranous staining, whereas the heterogeneous patterns (cytoplasmic and membranous) were considered as an aberrant E-cadherin expression.
We used Hep Par 1, glypican 3, and arginase 1 for confirmation of poorly differentiated HCC, MOC 31 for differentiation from cholangiocarcinoma, and CK 7 and CK 20 to exclude metastatic carcinoma.
The statistical package for the social sciences (SPSS) version 20 was used to analyze the data. The means and standard deviations of quantitative variables were used to describe them. The absolute frequencies of categorical variables were used to describe our data, and the Chi-square test and the Chi square for trend test were used to compare them. The Kaplan–Meier plot and Mantel–Cox test were used for comparing survival curves in two or more groups. Survival time meant the time to reach the event of interest or the time of follow-up. The level of statistical significance was set at P < 0.05. A highly significant difference was present if P ≤ 0.001.
| Results|| |
Clinical and pathological findings of the patients
We found that about 24% of the studied patients were ≤55 years old, 77.8% were males, 37% had tumor stage II, 51.9% had grade tumor II, 88.9% had absent lymph node metastasis. Vascular invasion and multi-focal metastasis occurred in 48.1% and 61.1% of our cases, respectively. HnRNP A1 high positivity was detected in 59.3% of the evaluated cases, whereas negative E-cadherin and ZEB 1 expression presented in 37% and 70.4% of the patients, respectively. Progression and death occurred in 75% and 61.1% of the patients, respectively, and regarding child class, 51.9% of the cases had child B [Table 1].
Relation between marker expression and different clinicopathological features
There is a statistically non-significant relation between HnRNP A1, ZEB1, and E-cadherin, with either age or gender of the studied patients. A statistically significant relation was present between HnRNP A1, ZEB1, E-cadherin, and each of progression, mortality, stage, grade, vascular invasion, lymph node involvement, number of metastases, and portal vein thrombosis [Table 2]. Histopathological features of HCC were demonstrated in [Figure 1], whereas variable expressions of HnRNP A1, ZEB 1, and E-cadherin in different grades of HCC are illustrated in [Figure 2], [Figure 3], [Figure 4], [Figure 5]. There is statistically significant association between OS and expression of HnRNP A1, ZEB 1, and E-cadherin [Table 4] and [Figure 6].
|Table 2: Relation between E-cadherin, ZEB 1, hnRNP, and both baseline characteristics and outcome of the studied patients|
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|Figure 1: (a) Well-differentiated HCC. (b) Poorly differentiated HCC (H&E x400)|
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|Figure 2: (a) Well-differentiated HCC with HnRNP A1 mild nuclear staining (immunoperoxidase, original magnification x100). (b) High power field of the previous case (immunoperoxidase, original magnification x400). (c) Poorly differentiated HCC with HnRNP A1 marked nuclear staining (immunoperoxidase, original magnification x100). (c) High power field of the previous case (immunoperoxidase, original magnification x400)|
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|Figure 3: (a) Well-differentiated HCC with ZEB1 mild nuclear staining (immunoperoxidase, original magnification x100). (b) High power field of the previous case (immunoperoxidase, original magnification x400). (c) Poorly differentiated HCC with marked ZEB1 nuclear staining (immunoperoxidase, original magnification x100). (d) High power field of the previous case (immunoperoxidase, original magnification x400)|
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|Figure 4: (a) Well-differentiated HCC with E-cadherine membranous staining (immunoperoxidase, original magnification x100). (b) High power field of the previous case (immunoperoxidase, original magnification x400). (c) Poorly differentiated HCC with aberrant E-cadherine staining (immunoperoxidase, original magnification x400)|
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|Figure 5: (a) Well-differentiated HCC with aberrant E-cadherine staining (immunoperoxidase, original magnification x100). (b) High power field of the previous case (immunoperoxidase, original magnification x400). (c) Well-differentiated HCC with negative E-cadherine staining (immunoperoxidase, original magnification x400)|
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|Table 4: Survival outcome in the studied patients with regard to marker expressions|
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|Figure 6: Kaplan–Meier plot; right panel for PFS and left panel for OS: (a) and (d) Stratified according to HnRNP A1 expression, (b) and (e) Stratified according to ZEB 1 expression, and (c) and (f) Stratified according to E-cadherin expression|
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Relation between marker expression and patients' outcome
The mean progression-free survival (PFS) in high HnRNP A1 expression was 12.9 ± 1.93 months versus 32.69 ± 2 months in low expression; the mean PFS in negative ZEB 1 expression was 23.48 ± 2.29 months versus 9.6 ± 2.69 months in positive expression, whereas the mean PFS in negative E-cadherin expression was 11.9 ± 6.83 months versus 24.46 ± 2.44 months in positive expression. Consequently, a statistically significant association between PFS and expression of HnRNP A1, ZEB 1, and E-cadherin was established.
The mean overall survival (OS) survival in high HnRNP A1 expression was 17.72 ± 1.9 months versus 34.77 ± 0.7 months in low expression, whereas the mean OS survival in negative ZEB 1 expression was 28.53 ± 1.68 months versus 15.5 ± 2.75 months in the positive expression status. Also, the mean OS in negative expression of E-cadherin was 16 ± 2.41 months versus 20.46 ± 1.93 months in positive-expressed patients.
With regard to treatment response, patients who exhibited positive ZEB1 and high HnRNP A1 expression had shown statistically significant progressive disease [Table 2]. However, non-significant relation between E-cadherin and treatment response was found.
There is significant negative correlation between ZEB 1 and each of E-cadherin and HnRNP A1 levels. There is significant positive correlation between E-cadherin and HnRNP A1 levels [Table 3].
| Discussion|| |
Despite recent developments regarding diagnostic and therapeutic methods, long-term survival of patients with HCC is still reduced because of the high recurrence rate after initial treatment.
HnRNP A1 has been shown to stimulate cancer cell proliferation and tumor angiogenesis through fibroblast growth factor 2 translation. Christofk et al. mentioned in their study that HnRNP A1 transcriptional upregulation resulted in a high PKM2/PKM1 ratio, leading to an alternative splicing event essential for tumor cell proliferation. Furthermore, by attaching to telomeric DNA regions, this HnRNP A1 may prevent tumor cells from approaching senescence.
Our patients were divided into two groups based on HnRNP A1 expression levels: high (n = 32/54) and low (n = 22/54). High levels of HnRNP A1 were linked to higher tumor grades (p < 0.001), advanced stages (p < 0.001), multi-focal metastases (p = 0.002), and the presence of portal vein thrombosis (p = 0.003). Furthermore, we exhibited a link between high HnRNP A1 expression and lower survival features.
In the current study, the mean PFS and OS in low HnRNP A1 expressions were longer than PFS and OS in patients who exhibited high HnRNP A1 expressions with a statistical significance (p value =< 0.001).
In agreement with our findings, Zhou et al. found that cases with tumor recurrence showed higher levels of HnRNP A1 expression than those without recurrence. Similarly, they observed higher overall survival rates among low HnRNP A1 patients than the high HnRNP A1 group. Moreover, they reported that HnRNP A1 expression was much higher in the highly metastatic cell lines (MHCC97H and HCCLM3) than in the poorly metastatic HCC cell lines, according to their western blots and qRT-PCR investigations.
Yang et al. revealed that HnRNP A1 and PKM mRNA expression in liver HCC was higher than in normal tissues. High HnRNP A1 expression in HCC is likely linked to more aggressive tumor features when taken together.
With regard to treatment response, a significant relation between HnRNP A1 and treatment response was found as no cases representing high HnRNP A1 achieved complete response (CR) and only 50% of them had partial response (PR). To our knowledge, no previous articles examined the relation between treatment response and HnRNP A1 expression.
In this study, ZEB 1 positive expression was found in 29.6% of our cases. We found non-significant relation between ZEB1 and either age or gender of the studied patients. In this study, a statistically significant relation was present between ZEB1 and each of progression, mortality, stage, grade, vascular invasion, lymph node involvement, response, and number of metastases (p value = 0.008, 0.001,0.001, 0.006,0.006, 0.01,0.056, 0.015, and <0.001, respectively). With regard to treatment response, patients who exhibited positive ZEB1 had shown statistically significant progressive disease (p value = 0.026).
Our results were similar to Chen et al., who found that ZEB1 was significantly higher in the HCC specimens than in the control specimens, and its expressions were positively associated with the number of tumors, tumor size, grades of differentiation, lymph node metastasis (LNM), and tumor node metastasis (TNM) stages. Moreover, they detected a reduced OS in ZEB1-positive patients compared with those not expressing it.
Parallel results by Qin et al. reported that tumors with high ZEB1 expression were significantly associated with advanced TNM stage and vascular invasion. Moreover, Sreekuma et al. found that ZEB1 expression was significantly associated with vascular invasion and tumor stage. As a result, they categorized ZEB1 expression as a significant independent marker of poor OS and DFS in HCC. According to Zhou et al., higher ZEB-1 expression was found in 65.4% of HCC tissues and was a strong predictor of poor overall and disease-free survival rates.
Zhou et al., who studied the expression of ZEB1 and PFKM in HCC, found that high expression of ZEB1 is correlated with poor prognosis of HCC. They also reported that ZEB1 promotes HCC development by activating the transcription of PFKM, establishing the direct link between ZEB1 promotion of glycolysis and the Warburg effect.
Hashiguchi et al. observed that positive ZEB-1 expression has been linked to aggressive disease, poor differentiation, development of metastases, and a poor clinical prognosis in colorectal carcinomas, endometrial malignancies, and prostate cancer.
In contrast, Chen et al. found high ZEB1 expression in 20.5% and preserved reaction in 79.5% of their studied cases, and ZEB1 did not show any prognostic significance; this difference may be the different antibody used.
Cadherins are transmembrane glycoproteins and primary mediators of calcium-dependent cellular adhesion being found in various locations: E-cadherin in epithelial tissues, N-cadherin in muscle and adult neural tissues, and P-cadherin in the placenta. E-cadherin and β-catenin have an active role in the regulation of epithelial cell adhesion, being closely related to cancer invasiveness.
We found a statistically non-significant relation between E-cadherin and either age or gender of the studied patients. A statistically significant relation was present between E-cadherin and each of progression, mortality, stage, grade, vascular invasion, lymph node involvement, response, number of metastases, and portal vein thrombosis (p value 0.036, 0.006, 0.016, 0.001, 0.006, 0.022, 0.005, 0.002, and 0.028, respectively). With regard to treatment response, non-significant relation between E-cadherin and treatment response was found.
Amadeus et al. study detected more frequent positive E-cadherin reaction in trabecular/sinusoidal and acinar HCC than the clear cell subtype. Notably, positive E-cadherin immunostaining was significantly higher in tumors associated with capsular infiltration.
Similarly, Wei et al. found a statistically significant relation between E-cadherin and grade of HCC as reduced E-cadherin immunostaining was observed in poorly differentiated cancers.
In contrast, Endo et al. reported that E-cadherin and β-catenin expressions were inversely correlated with the degree of tumor differentiation, being considered useful markers for HCC differentiation.
We observed that the mean PFS and OS in negative E-cadherin expression were shorter than those in positive E-cadherin expression with significance (p value = 0.003, <0.001), respectively.
Chen et al. demonstrated that reduced expression of E-cadherin was correlated with reduced survival at 1, 3, and 5 years in patients with HCC; also, it was significantly correlated with the presence of metastases, vascular invasion, a low degree of differentiation, and advanced TNM stages. Therefore, E-cadherin expression appears to have predictive potential for patients diagnosed with HCC; these findings completely agree with the current study.
When studying the relation between all three markers and each other, we found a significant negative correlation between ZEB 1 and E-cadherin. Our finding was supported by Zhou et al., who observed, by using western blot, a significant correlation between lower E-cadherin protein expression and elevated ZEB-1 expression in HCC specimens. Moreover, Jia et al. reported that ZEB-1 inhibits the E-cadherin gene, resulting in a drop in E-cadherin levels and an increase in cancer cell migration and invasiveness. In addition, Zeisberg and Neilson found that ZEB-1 and ZEB2 interact with the E-box element within the proximal region of the E-cadherin promoter causing its inhibition.
Thakur et al. and Aigner et al. concluded that ZEB1 can act as a driver of EMT through the inhibition of E-cadherin expression and the activation of the Fak/Src signal pathway.
In the current study, the mean PFS in negative ZEB 1 and low HnRNP A1 expressions were longer than the PFS in patients who exhibited positive ZEB 1 and high HnRNP A1 expressions with statistical significance (p value =<0.001) for both; this was consistent with Hashiguchi et al., who evaluated the relation between expression patterns of ZEB-1 and E-cadherin and OS in HCC. They reported that patients with ZEB-1-positive and reduced E-cadherin expression showed a significantly poorer prognosis, and reduced expression of E-cadherin was significantly associated with increased intra-hepatic metastasis.
Our study limitations were in the form of a small sample size and retrospective study design. We are aware of the small number of patients we have, but their placement in one institution in the same Governorate allows for more consistency in case management and, as a result, in the results produced. Therefore, more research is needed to confirm the prognostic relevance of the evaluated markers.
| Conclusion|| |
The results we obtained suggest that HnRNP A1 and ZEB1 are poor prognostic factors of HCC patients associated with progression, mortality, stage, grade, vascular invasion, lymph node involvement, response, number of metastases, and portal vein thrombosis. E-cadherin has an important role in the development of differentiated forms of HCCs and favorable outcome. Proper pathway understanding of these markers may be implicated in novel treatment philosophy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Nehal S Abouhashem
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4]
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