Abstract
Introduction
Hepatocellular carcinoma (HCC) carcinogenesis is not yet fully known. Insulin-like growth factor-1 receptor (IGF-1R) can translocate to the nucleus and modulate cellular growth, possibly participating in HCC development and aggressiveness. This study aimed to evaluate the immunoexpression of IGF-1R in HCC, the cellular compartment involved, and its association with clinicopathological parameters and clinical outcomes.
Methods
Liver specimens from 111 HCC patients who underwent liver transplantation or partial surgical resections at a Brazilian referral hospital center were studied. IGF-1R expression was determined by immunohistochemistry, clinical data were collected from medical records, and pathological parameters were obtained from path review.
Results
IGF-1R nuclear expression was higher in the tumor than in the adjacent cirrhosis (p < 0.001). The odds of IGF-1R expression in the nucleus compared to the membrane are lower in the cirrhosis condition than in the tumor, suggesting an increase in the prevalence of nucleus expression relative to the membrane from cirrhosis to tumor. There was an association between IGF-1R nuclear expression in HCC and the moderate/poor grade of histologic differentiation (p < 0.001). However, long-term clinical outcomes were not associated with IGF-1R nuclear expression.
Conclusion
The data presented here suggest the role of IGF-1R in HCC progression and carcinogenesis as its expression increases in the nucleus relative to the membrane, from cirrhosis to tumor, and it was associated with a poorer differentiated tumor grade. Further research is awaited to fully understand the mechanisms underlying this association.
Keywords: Insulin-like growth factor-1 receptor, Nuclear expression, Hepatocellular carcinoma, Cirrhosis
Introduction
Hepatocellular carcinoma (HCC), the most common primary malignant neoplasia of the liver, ranks the sixth most common malignancy and the third leading cause of cancer mortality worldwide. This complex and heterogeneous disease is caused by chronic liver disease (CLD) of different etiologies, such as hepatitis B (HBV) or C (HCV) viruses and alcohol-induced liver damage, having cirrhosis as the anatomic substrate in most cases [1, 2]. Despite many advances in HCC management in the last decade, the overall prognosis of HCC remains dismal. A better understanding of the complex mechanisms involved in hepatocarcinogenesis, including critical alterations in protein expression, may improve this scenario [3, 4].
The role of intracellular signaling pathways, such as the MAPK (mitogen-activated protein kinase) and the PI3K/AKT/mTOR, has been under intense debate in HCC. The activation of proteins in these cascades elicits cellular events related to proliferation, tumor angiogenesis, and apoptosis inhibition. In this context, receptors of growth factors are recognized as one of the main steps for signal transduction abnormalities. Among them, the insulin-like growth factor-1 receptor (IGF-1R) stands out [5–9].
This tyrosine kinase transmembrane receptor harbors 70% of its homology to the insulin receptor, and its ligands are produced under growth hormone stimulation. Its activation mediates various pathological processes, as seen in the carcinogenesis of different tumors, such as HCC [10–12]. Current evidence has demonstrated an intriguing IGF-1R particularity: its ability to translocate to the nucleus. This phenomenon suggests a direct control of gene transcription, including those involved in the progression of the cell cycle and self-regulation of the IGF-1R gene. In this mechanism, the receptor could modulate cellular growth to the point of genomic control, contributing to neoplastic transformation [13].
Characteristic alterations in the IGF-1R axis, detected in HCC and hepatoma cell lines, have emerged as important events in malignant transformation and the growth of tumors [14]. Apart from its involvement in carcinogenesis, IGF-1R overexpression, as well as its nuclear expression, may have a prognostic value, as demonstrated in several malignancies, such as colorectal cancer [15], non-small cell lung cancer [16], and multiple myeloma [17]. A better understanding of this mechanism in HCC could translate into improvement in the management of this complex disease.
Since HCC represents the outcome of CLD natural history from fibrosis to cirrhosis and finally to cancer, molecular heterogeneity may occur in each different step of this sequence [18]. Thus, a comparative analysis between the events of the tumor and the underlying cirrhosis might add evidence to the challenging landscape of hepatocarcinogenesis. Therefore, this study aims to comprehensively assess the IGF-1R expression in tumor and adjacent cirrhotic parenchyma and its association with clinical and pathological HCC parameters, including long-term outcomes.
Materials and Methods
Cohort
From 2000 to 2020, 111 (n = 111) patients who underwent liver transplantation or partial surgical resections as treatment of HCC at the Hospital das Clínicas, a referral center in Brazil, were selected for the study. Clinical data were collected from medical charts. The pathological review was performed by two experienced pathologists, who were blinded to the details of the patients, and the results were determined based on their agreement. Inclusion criteria were as follows: (1) liver specimens for pathological review and (2) coexistence of HCC and underlying chronic liver disease. It excluded patients with synchronic tumors, fibrolamellar variants, and autoimmune CLD etiology. The Ethics Committee approved this study (CAAE – 44573615.7.0000.5149), and written informed consent was obtained from the patients or their relatives.
Preparation of Tissues and Immunohistochemical Analysis
The specimen slides were reviewed to choose the most representative paraffin blocks, from which sections of 3 µm thickness were taken and placed on salinized slides. The histological sections were dewaxed in xylene and dehydrated with graded ethanol. They were then immersed in a 1 mm EDTA (pH 8.0) solution and heated to 96°C in a vaporizer steamer for antigen retrieval. After cooling and washing the samples with buffer TRIS, 0.05 m Tris-HCL (pH 7.6), endogenous peroxidase activity was blocked with 3% H2O2 in water for 15 min. Then, the sections were incubated with primary antibody anti-IGF-1R (Abcam, ab39675) for 60 min. It was followed by incubation with the EnVision™ Dual Link System (Dako). Next, peroxidase activity was developed with 3.3-diaminobenzidine (DAB) (Sigma, St. Louis, MO, USA) with timed monitoring using a positive control sample. Then, the sections were counterstained with hematoxylin and treated with the Bluing reagent (Thermo Scientific). Negative controls, in which primary antibodies were omitted, showed no specific staining. The positive control was obtained as indicated in the user manual of the primary antibody. Staining was considered positive when present in more than 10% of the cell compartment, even if in weak intensity. The protein expression and the cellular compartment involved were assessed by immunohistochemistry (IHQ) in both tumor and underlying cirrhosis. Comparative analysis between groups that expressed or did not express IGF-1R was performed.
Demographic, Clinical, and Pathological Data
All patients whose samples were analyzed and selected had their medical records reviewed. Information regarding clinicopathological parameters, such as gender, age at diagnosis, number of tumor nodules, size of the largest tumor nodule, tumor grade, etiology of the CLD, presence of angiolymphatic invasion, alpha-fetoprotein (AFP) serum level, and MELD score (model for end-stage liver disease) was collected. For survival analysis, the event was defined as tumor recurrence or death from any cause, whichever occurred first, within the follow-up period (December 15, 2020). Event-free survival (EFS) was considered as the interval between liver transplantation or partial liver resection and the event’s occurrence or the end of the follow-up period, which occurred first.
Statistical Analysis
Descriptive statistics were used to summarize the data. The values of continuous variables were described in the tables as medians and interquartile ranges, and a normality test (Shapiro-Wilk) was performed. The continuous variable was submitted to the Mann-Whitney test. The χ2 test or Fisher’s test was performed to identify the association between categorical variables when necessary. The univariate and multivariate Poisson regression model with covariance structure was performed to determine the characteristics independently associated with the IGF-1R nuclear expression. Kaplan-Meier curves were performed for survival analysis, and a log-rank test was used to compare curves. Statistical significance was assumed at p < 0.05. The SPSS Statistics program (IBM Corp., 2015, IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY, USA: IBM Corp.) was used for statistical analysis.
Results
Of the 111 patients whose samples were analyzed, 13 (11.7%) showed positive nuclear immunohistochemical staining for IGF-1R in the cirrhosis area and 38 (34.2%) in the HCC area. Of those positive in cirrhosis parenchyma, 11 (84.6%) were also positive in the tumor, as exemplified in Figure 1. When comparing the positivity in cirrhosis with the tumoral areas, the IGF-1R nuclear expression was more often observed in the tumor (p < 0.001).
Fig. 1.
a IGF-1R nuclear labeling absent in HCC (left) and absent in adjacent cirrhotic liver (right) (magnification, ×100). b IGF-1R nuclear labeling present in the HCC (lower left region) and absent in the adjacent cirrhotic liver (upper right region) (magnification, ×50). c Nuclear labeling of IGF-1R in the cirrhotic liver (magnification, ×200). d Nuclear labeling of IGF-1R in the HCC (magnification, ×400).
The association between IGF-1R nuclear expression in cirrhosis and its association with cirrhosis etiology and MELD is shown in Table 1. In the present study, cirrhosis caused by HBV seemed to be associated with the nuclear expression of the receptor in the cirrhotic parenchyma in the univariate analysis (p < 0.01) but not in the multivariate analysis. The association between IGF-1R nuclear expression in HCC with clinical and anatomopathological parameters was also investigated and is presented in Table 2. Of those cases positive in the HCC area, 7 (18.4%) had well-differentiated histology, and 31 (81.6%) were moderately/poorly differentiated. The moderate/poor differentiation grade was found to be independently associated with the IGR-1R nuclear expression in the tumor, as shown in the multivariate analysis (p < 0.001). No other clinical or pathological parameter investigated was independently associated with the IGF-1R nuclear staining in HCC.
Table 1.
Association between clinical and anatomopathological characteristics and nuclear expression of IGF-1R in cirrhotic parenchyma
| Variable | Nuclear expression of IGF-1R in cirrhotic parenchyma | p value | |
|---|---|---|---|
| absent | present | ||
| Etiology of cirrhosis, n (%)a | 0.003* | ||
| Hepatitis C | 47 (42.30) | 2 (1.80) | |
| Cryptogenic | 17 (15.30) | 2 (1.80) | |
| Ethanolic | 17 (15.30) | 1 (0.90) | |
| Hepatitis B | 12 (10.80) | 6 (5.40) | |
| Autoimmune | 3 (2.70) | 0 (0) | |
| NAFLD | 0 (0) | 2 (1.80) | |
| Hemochromatosis | 2 (1.80) | 0 (0) | |
| MELD value, median (IQR)c,b | 20 (14.75–24.00) | 16 (16–20) | 0.491 |
Data are expressed as absolute numbers (percentage) and median (IQR).
Number of patients with the characteristic/number for whom the information was available.
IQR, interquartile range; NAFLD, nonalcoholic fatty liver disease; MELD, model for end-stage liver disease.
The test used: aχ2 test.
bFisher’s exact test.
cScore obtained in 77 cases.
*p value <0.01.
Table 2.
Association between clinical and anatomopathological characteristics and nuclear expression of IGF-1R in HCC
| Variable | Nuclear expression of IGF-1R in HCC | p value | |
|---|---|---|---|
| absent | present | ||
| Tumor differentiation, n (%)a | <0.001* | ||
| Well differentiated | 47 (42.30) | 7 (6.30) | |
| Moderately/poorly differentiated | 26 (23.40) | 31 (27.90) | |
| Vascular invasion, n (%)b | 0.659 | ||
| Present | 5 (4.50) | 0 (0) | |
| Absent | 68 (61.20) | 38 (34.20) | |
| Number of nodules, n (%)b | 0.978 | ||
| 1 | 38 (34.20) | 21 (18.90) | |
| 2 | 18 (16.20) | 8 (7.20) | |
| 3 | 5 (4.50) | 1 (0.90) | |
| 4 | 6 (5.40) | 3 (2.70) | |
| 5 | 1 (0.90) | 1 (0.90) | |
| 7 | 1 (0.90) | 1 (0.90) | |
| 10 or more | 4 (3.80) | 3 (2.70) | |
| Etiology, n (%)b | 0.708 | ||
| Hepatitis C | 33 (29.70) | 16 (14.40) | |
| Cryptogenic | 12 (10.80) | 7 (6.30) | |
| Ethanolic | 11 (9.90) | 7 (6.30) | |
| Hepatitis B | 12 (10.80) | 6 (5.40) | |
| Autoimmune | 3 (2.70) | 0 (0) | |
| NAFLD | 0 (0) | 3 (2.70) | |
| Hemochromatosis | 2 (1.80) | 0 (0) | |
| Size of the largest nodule, median (IQR), cmc | 3.00 (1.20–4.00) | 3.00 (1.16–4.20) | 0.855 |
| MELD value, median (IQR)d,c | 20 (14.75–24.00) | 20 (7–32) | 0.893 |
| AFP, median (IQR), ng/mLe,c | 11.40 (3.97–42.55) | 8.90 (3.55–56.55) | 0.790 |
Data are expressed as absolute numbers (percentage) and median (IQR).
Number of patients with the characteristic/number for whom the information was available.
IQR, interquartile range; NAFLD, nonalcoholic fatty liver disease; AFP, alpha-fetoprotein; MELD, model for end-stage liver disease.
The test used: aχ2 test.
bFisher’s exact test.
cMann-Whitney test.
dScore obtained in 77 cases.
eSerum level identified in 86 cases.
*p value <0.001.
Another analysis compared the expression of IGF-1R in the membrane to the nucleus in normal livers, HCC tumor cells, and the adjacent cirrhotic parenchyma. In the control group (n = 8), membrane IGF-1R expression was present in all cases in the normal liver. Nuclear expression, otherwise, was positive in a smaller number, with a proportion of 0.25. In cirrhosis, the proportion of positivity for IGF-1R in the membrane was 0.58 and in the nucleus was 0.12. Whereas in tumor parenchyma, the proportion of positivity in the membrane was 0.50 and in the nucleus was 0.34. We observed that the proportion of cases with IGF-1R membrane expression is lower in the tumor than in the cirrhosis condition. Furthermore, the proportion of nuclear expression is higher in tumors than in cirrhosis. Regarding the comparison between tumor and cirrhosis, the odds ratio for nuclear expression compared to the membrane in the tumor was 0.53 (95% confidence interval: 0.31–0.90), and in cirrhosis was 0.10 (95% confidence interval: 0.05–0.20), as illustrated in Figure 2.
Fig. 2.
Comparison of the expression of IGF-1R in the membrane and the nucleus in the normal liver, HCC tumor cells, and the adjacent cirrhotic parenchyma.
Finally, the influence of IGF-1R expression on HCC long-term outcomes was investigated. HCC recurrence was identified in 11 (10.70%) of the 102 patients whose follow-up data were available. Clinically proven recurrence followed by death was documented in eight of these patients. The event rate was 30.40% (31 relapses or deaths from any cause of the 102 patients analyzed). Nine patients were lost to follow-up. No significant difference was identified between recurrence, death, event-free time, and nuclear positivity for IGF-1R in HCC or cirrhotic parenchyma, as shown in Table 3. In the survival analysis, the median EFS was 65 months. The overall EFS rate at 12 and 24 months was 84.00% and 80.60%, respectively. When analyzing the presence of IGF-1R nuclear immunoexpression in tumor and cirrhosis and survival plots, the Kaplan-Meier curves showed overlap (log-rank test p = 0.667 and p = 0.589, respectively), as illustrated in Figure 3.
Table 3.
Clinical outcomes according to IGF-1R nuclear expression in cirrhotic parenchyma and HCC
| Nuclear expression of IGF-1R in cirrhotic parenchyma | p value | ||
|---|---|---|---|
| absent | present | ||
| Recurrence | 8/102 (7.80) | 3/102 (2.90) | 0.050 |
| Death | 22/102 (21.50) | 3/102 (2.90) | 0.831 |
| EFS, months | 49.50 (12.00–96.25) | 26.50 (15.00–72.00) | 0.252 |
| Nuclear expression of IGF-1R in HCC | p value | ||
|---|---|---|---|
| absent | present | ||
| Recurrence | 7/102 (6.80) | 4/102 (3.90) | 0.744 |
| Death | 18/102 (17.60) | 7/102 (6.80) | 0.684 |
| EFS, months | 49.0 (12.00–109.50) | 35.00 (12.00–80.00) | 0.249 |
Data are expressed as absolute numbers (percentage) or median (interquartile range).
Number of patients with analyzed outcome/number for whom the information was available.
EFS (event free survival), event was defined as recurrence or death from any cause since liver transplantation or resection.
The test used: Fisher’s exact test.
Fig. 3.
Comparison of Kaplan-Meier curves among patients with nuclear IGF-1R expression in the cirrhotic liver (a) and HCC (b).
Discussion
In this study, the IGF-1R was expressed both in HCC and adjacent cirrhotic parenchyma, and this event occurred in different cellular compartments – nucleus and membrane. The proportion of cases with IGF-1R expression in the membrane is lower in the tumor than in the cirrhosis, but nuclear labeling is higher in the tumor than in cirrhosis. Additionally, the moderate or poor grade of tumor differentiation was independently associated with the nuclear pattern of this receptor expression.
Hepatocarcinogenesis is a multistep process determined by environmental and genetic changes, whose mechanisms are still poorly understood. However, some intracellular signaling pathways, such as the MAPK and the PI3K/AKT/mTOR pathway, have an increasingly well-established role. More recently, studies have addressed the contribution of the IGF-1R nucleus translocation process to neoplastic transformation, clinical behavior, and increased resistance to drugs used to treat HCC [12, 18]. The present study is the first to analyze the expression of this receptor in HCC and cirrhosis. It is also the first to correlate this expression with pathological and clinical data.
Zhang et al. [3] demonstrated a significantly higher immunohistochemical membrane expression of IGF-1R in HCC than in adjacent cirrhosis. Yan et al. also observed, when analyzing animal models, an increase in IGF-1R and IGF-1R mRNA expression at different stages of malignant HCC transformation, identifying increasing levels as the normal liver progresses to a precancerous state and ultimately to HCC [12, 19]. Few studies have evaluated the nuclear immunoexpression of IGF-1R in HCC. However, nuclear IGF-1R translocation could further contribute to cell proliferation. Warsito et al. [20] observed that nuclear IGF-1R could associate with lymphoid enhancer-binding factor 1 (LEF1) in the cell nucleus, leading to an increase in cyclin D1 levels, which suggests that nuclear IGF-1R could be responsible for aberrant cell cycle progression.
In the present study, we demonstrate that the odds of IGF-1R expression in the nucleus compared to the membrane are lower in the cirrhosis condition than in the tumor, suggesting an increase in the prevalence of nucleus expression relative to membrane expression from cirrhosis to tumor. It means that, during the disease progression, there may be a shift in the expression of IGF-1R in the nucleus relative to the membrane in the tumor, compared with adjacent cirrhosis. Together, data suggest that, through its nuclear translocation, IGF-1R may participate even in the early steps of hepatocarcinogenesis since the development of HCC occurs sequentially from cirrhosis to dysplastic nodules and finally to neoplasia. It might help differentiate between cirrhosis and early tumor, harbor a prognostic value, and be a potential target for new directed therapies. Nuclear expression, otherwise, was positive in a smaller proportion of cases in the control group, which was not expected when we assumed that nuclear expression increases with disease progression. We want to emphasize that our work was carried out in a population with a high prevalence of CLD, so we cannot assert that the control group was completely normal livers. This bias may have influenced the data obtained. Further research is necessary to understand the mechanisms underlying this event.
In a study carried out by our research group, a higher expression of MAPK pathway proteins was identified mainly in HCCs that arise in the context of viral CLD. It is known that the activation of this pathway can be elicited by different mechanisms, which include IGF-1R stimulation [21]. Recent evidence has shown that the transactivating protein X, expressed by HBV, may play a key role in hepatocarcinogenesis and correlate with a higher probability of metastases in patients with HCC associated with HBV [22–24]. Kim et al. [25] also demonstrated that the transactivating protein X could increase the expression of IGF-1R. In the present study, an association of nuclear IGF-1R expression was shown in cirrhosis caused by HBV in the univariate analysis, but the multivariate analysis did not identify this etiology as an independent parameter. These data could be better explored in studies with more HBV-related HCC patients. The reduced representability of the HBV group reflects the wide availability of vaccination and easier access to antiretroviral treatment in Brazil, where its prevalence has decreased.
Many studies have shown a correlation between the expression of IGF-1R and a worse clinical outcome and more aggressive behavior in different tumors [15–17]. It is known that the degree of tumor differentiation correlates with more aggressive behavior of the malignancy and worse prognosis. In a study by Tamura et al. [26], the histological degree of HCC differentiation was an independent prognostic factor. It is also well known that a worse degree of differentiation shows a relationship with larger, more advanced tumors and has a higher recurrence rate, indicating an important association with worse prognosis and other clinical and anatomopathological findings [27]. The present study also assessed the association of IGF-1R with clinical and pathological indices. Higher nuclear expression of IGF-1R was demonstrated in poorly and moderately differentiated tumors. When analyzing the IGF-1R hyperexpression in the membrane of tumor cells, Kang et al. [28] showed its correlations with higher degrees of HCC differentiation.
Despite being associated with this prognosis parameter, the expression of IGF-1R was not associated with poor clinical outcomes. There were no differences in overall and EFS when comparing groups that expressed or did not have the receptor in the nuclei of tumor cells. We have raised some considerations that may explain this finding. Our study included patients in the initial stages of the disease since they were candidates for surgical treatment or liver transplantation. Thus, the proportion of small HCCs may have influenced this study’s overall survival of poorly differentiated tumors. Shinkawa et al. [29] have demonstrated that tumor size affects the behavior of poorly differentiated tumors, with a higher impact on overall survival in those patients with tumors measuring up to 5.0 cm. The prognostic value of the IFG-1R nuclear expression may become more evident in larger tumors and advanced stages. Moreover, many patients in our cohort were submitted to partial resection. Those patients did not have a clinical follow-up with the same frequency as those undergoing liver transplantation, which may affect the survival analysis and assessment of outcomes.
Regarding other pathological and clinical aspects, the number of nodules, the size of the largest nodule, the presence or absence of vascular invasion, the MELD score, and AFP serum levels were evaluated. No statistically significant difference was observed regarding the nuclear expression of IGF-1R in the tumor or the cirrhotic parenchyma and those parameters.
Among the limitations of our study include those related to sample size and possible information bias, characteristic of retrospective studies. Data collection took place before the implementation of electronic records, which brought issues in filling out important information, such as MELD score and AFP levels. In addition, patients undergoing partial resection did not have a clinical follow-up with the same frequency as those undergoing liver transplantation, which may affect the survival analysis and assessment of outcomes. Among those who died, recurrence may have occurred without being diagnosed. Another limitation concerns the differences in treatment at the time of recurrence and after progression among patients. Our study was unicentric, and every patient had the same resources available for systemic and local treatment. The resources were equally limited since the patients were from the public health system. We assumed that there were no heterogeneities regarding treatment offered and thus had little impact on overall survival analysis.
The data presented here suggest an increasing expression of IGF-1R in the nucleus relative to the membrane, from cirrhosis to tumor, suggesting its role in disease progression and carcinogenesis. This expression pattern was associated with a poorer differentiated tumor grade, but no association with relevant clinical outcomes was demonstrated. Notably, further research is awaited to fully understand the mechanisms underlying this association and investigate its value as a diagnostic and prognostic tool in HCC.
Acknowledgments
We thank Mrs. Fernanda C.S. Barros for technical assistance.
Statement of Ethics
The Research Ethics Committee – Federal University of Minas Gerais reviewed and approved this study protocol, approval number CAAE 44573615.7.0000.5149. All patients provided a signed informed consent form at the time of surgical liver resection. The study was conducted according to the tenets of the Declaration of Helsinki.
Conflict of Interest Statement
The authors declare no conflicts of interest.
Funding Sources
This study was supported by Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG), and no funds or grants were received during the preparation of this manuscript.
Author Contributions
Maria Maia: data curation, formal analysis, investigation, methodology, validation, and writing – original draft; Ronniel Albuquerque: data curation, formal analysis, investigation, writing – original draft, and writing – review and editing; Serena Silva: investigation, methodology, and visualization; Cristiano Lima: supervision, validation, and writing – review and editing; Paulo Diniz: conceptualization, formal analysis, investigation, supervision, writing – original draft, and writing – review and editing; and Paula Vidigal: conceptualization, funding acquisition, project administration, validation, and writing – review and editing.
Funding Statement
This study was supported by Fundação de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG), and no funds or grants were received during the preparation of this manuscript.
Data Availability Statement
All data analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.
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Associated Data
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Data Availability Statement
All data analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.