DOI: 10.18585/inabj.v16i5.3324

ERβ and IL-6 Expression in CRC Tumor Differentiation (Theodora I, et al.)
Indones Biomed J. 2024; 16(5): 481-6

RESEARCH ARTICLE

Tumor Differentiation is Correlated with Estrogen Receptor Beta (ERβ)
Expression but Not with Interleukin-6 (IL-6) Expression in Colorectal Carcinoma
Imelda Theodora1,2, I Ketut Sudiana1,, Vicky Sumarki Budipramana3,4, Ferdinand Erwin5,
Sianty Dewi6, Bernadette Dian Novita7
2

1
Doctoral Program of Medical Science, Faculty of Medicine, Universitas Airlangga, Jl. Prof. Dr. Moestopo No. 47, Surabaya 60132, Indonesia
Department of Pathology, Faculty of Medicine, Widya Mandala Surabaya Catholic University, Jl. Kalisari Selatan No. 1, Surabaya 61112, Indonesia
3
Department of Surgery, Faculty of Medicine, Universitas Airlangga, Jl. Prof. Dr. Moestopo No. 47, Surabaya 60132, Indonesia
4
Department of Surgery, Dr. Soetomo General Academic Hospital, Jl. Prof. Dr. Moestopo No. 6-8, Surabaya 60132, Indonesia
5
Faculty of Medicine, Widya Mandala Surabaya Catholic University, Jl. Kalisari Selatan No. 1, Surabaya 61112, Indonesia
6
Department of Obstetric and Gynecology, Faculty of Medicine, Widya Mandala Surabaya Catholic University, Jl. Kalisari Selatan No. 1,
Surabaya 61112, Indonesia
7
Department of Pharmacology and Therapy, Faculty of Medicine, Widya Mandala Surabaya Catholic University, Jl. Kalisari Selatan No. 1,
Surabaya 61112, Indonesia

*Corresponding author. Email: i-ketut-s@fk.unair.ac.id
Received date: Sep 10, 2024; Revised date: Oct 21, 2024; Accepted date: Oct 24, 2024

Abstract

B

ACKGROUND: Colorectal carcinoma (CRC), the third most common malignant disease worldwide, is associated
with estrogen receptor β (ERβ) and interleukin-6 (IL-6). ERβ is known to down-regulate IL-6 in prostate cancer,
lung carcinoma, and CRC cell lines; however, its effect on human with CRC remains unclear. Therefore, this study
was conducted to investigate the association between ERβ and IL-6 expressions with the clinicopathological features of CRC.
METHODS: This was an analytic observational study using 40 paraffin blocks of CRC patients. ERβ and IL-6 expression
was measured by immunohistochemistry (IHC) staining. The percentage of immunoreactive tumor cell per 1000 cells was
manually recorded and tumor differentiation as well as tumor infiltration were determined. Tumor differentiation was graded
according to the World Health Organization (WHO) 2010 criteria, while tumor infiltration was defined based on the American
Joint Committee on Cancer (AJCC) 8th edition.
RESULTS: Fifty percent of samples were well-differentiated CRC, and 57.5% samples were T3 infiltration tumors. IHC
staining showed 35.5% of samples were positive for ERβ expression, while 70.86% were positive for IL-6 expression. There
were negative correlation of ERβ expression with tumor differentiation (p=0.018; r=-0.371), but no correlation with tumor
infiltration (p=0.836) were found. There was no correlation between ERβ expression with IL-6 expression (p=0.154).
CONCLUSION: There is statistically significant correlation between tumor differentiation and ERβ expression, wherein
improved tumor differentiation is linked to higher levels of positive ERβ expression. However, there is no discernible
relationship between IL-6 and tumor differentiation. These findings suggest that while IL-6 was involved in the growth of the
tumor, ERβ expression might have an impact on tumor differentiation.
KEYWORDS: colorectal carcinoma, estrogen receptor beta, interleukin-6, cell differentiation
Indones Biomed J. 2024; 16(5): 481-6

Introduction

The number of colorectal carcinoma (CRC) cases has been
rising, ranking third globally in 2018, with 1.8 million new

cases per year (10.2%).(1) CRC ranks as the third most
prevalent type of cancer CRC is also the second leading
cause of cancer-related deaths across the globe.(2) The
incidence of CRC is 30% higher in men than in women, with
men also showing an earlier onset and a higher prevalence of

Copyright © 2024 The Prodia Education and Research Institute.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC-BY-NC) License.

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The Indonesian Biomedical Journal, Vol.16, No.5, October 2024, p.397-486

adenomas.(3) Some studies also indicates that CRC is more
prevalent in men than women. This fact leads to a suspicion
regarding estrogen’s effect on the development of CRC.
Studies suggest an inverse relationship between estrogen
receptor beta (ERβ/ESR2) and the incidence of colorectal
polyps and tumor stages, potentially offering a protective
effect. About two-thirds of sporadic CRC cases arise from
adenomas with polypoid features.(1,2) Both lab and human
trials have shown that substances like phytoestrogens and
drugs targeting ERβ can trigger these receptors, promoting
cell death and reducing CRC incidence.(4,5) This
underscores the protective role of estrogen against CRC.
Pro-inflammatory cytokines, such as interleukin
(IL)-6, have also been linked to increased CRC risk and
tumor progression.(6,7) Inflammation raises free radical
levels, leading to DNA damage and potential neoplastic
transformation.(8,9) However, the precise mechanism of
CRC development involving the estrogen receptor and
IL-6 pathway remains unclear. Early detection methods,
including identifying prognostic biomarkers and developing
new therapies, are crucial for CRC. Further research on
ERβ and IL-6 expressions in CRC development is needed
to determine which pathway is more dominant and whether
there is a connection between ERβ and inflammation via
IL-6. If such association exists, ERβ and IL-6 might become
the next therapeutic targets and prognostic biomarkers for
CRC patients.
Various
therapies
including
chemotherapy,
radiotherapy, or surgery, faced some difficulties in combating
cancer cells.(10) Several studies suggest that drugs like
estrogen, which is used in postmenopausal hormone
replacement therapy, and non-steroidal anti-inflammatory
drugs (NSAIDs) such as aspirin, may help preventing the
development of CRC. Cohort studies indicate that regular,
long-term use of aspirin and other NSAIDs can reduce
CRC risk. However, the American Cancer Society does not
recommend NSAIDs for cancer prevention due to some risks
such as gastrointestinal bleeding. Similarly, postmenopausal
hormone therapy is not advised for CRC prevention, as it
may increase breast cancer and cardiovascular disease risks.
Currently, the American Cancer Society advises against
using drugs or supplements for CRC prevention because
the correct dosage, effectiveness, and potential toxicity
are unclear.(11) Although estrogen may influence CRC
proliferation and suppression, the exact pathways remain
unknown, prompting further research into its association
with the inflammatory process in CRC development.
ERβ is the dominant estrogen receptor in the colon
mucosa.(12) Research using CRC cell lines with ERβ shows
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that it can down-regulate IL-6 through NF-κβ in SW480
cells. Estrogen has been shown to reduce IL-6 expression
in various cell line cultures by inhibiting protein binding
in NF-κβ.(13) In multiple myeloma, estrogen inhibits
IL-6-induced cell proliferation.(14) Estrogens may have
anti-tumor effects by selectively activating ERβ-mediated
pro-apoptotic signals, inhibiting inflammatory signals, and
modulating the tumor microenvironment.(15,16) Even
though, understanding the interaction between ERβ and IL-6
in CRC is important to consider the usage of ERβ agonist
(Silymarin) and IL-6 inhibitors in CRC as targeted therapy,
unfortunately limited studies are available to explain
the mechanism. Therefore, this study was conducted to
investigate the differences and correlation of ERβ and IL-6
expressions in the development of CRC in term of tumor
differentiation and tumor infiltration.

Methods

Study Design and Samples Collection
This was an analytic observational study with cross-sectional
design using 40 paraffin blocks of CRC patients that were
obtained from the Anatomical Pathology Department of
Dr. Soetomo General Hospital, Surabaya. Paraffin blocks
of resected CRC patients that were in good condition were
included as samples in this study. However, paraffin blocks
of patients who received neoadjuvant chemotherapy and
patients diagnosed with mucinous adenocarcinoma colon
were excluded. Samples that met the inclusion and exclusion
criteria further randomized and analyzed for the expression
of ERβ and IL-6.
The protocol of this study was reviewed and approved
by the Ethical Review Committees of Dr. Soetomo General
Hospital (Ref No. 0461/LOE/301.4/V/2021). This study
has also been registered in ClinicalTrial.gov ID (No.
NCT05202548). Since in this study samples were taken
from the remaining material of a pathology laboratory
specimen, hence no explicit formal informed consent was
obtained from patients according to hospital protocol.
Immunohistochemistry (IHC) Analysis for ERβ and
IL-6 Measurement
Each specimen was cut into 5 µm-thick parallel sections and
stained with hematoxylin and eosin. After deparaffinization
and rehydration, the sections were briefly microwaved for
antigen retrieval using citrate buffer, pH 6·0, at 750 W for
10 minutes, and at 350 W for 15 minutes. After being cooled
down for 20 minutes at room temperature, the sections were

DOI: 10.18585/inabj.v16i5.3324

incubated with hydrogen peroxide for 10-15 minutes and
then washed two times with buffer. Then, the sections were
incubated separately with primary antibodies according
to the manufacturer’s protocol. The Anti ERβ Polyclonal
Antibody (Cat. No. bs-0255R; Bioss Antibodies, Woburn,
MA, USA) and Anti-IL-6 Monolyclonal Antibody (Cat. No.
E-AB-30095; Elabscience, Houston, TX, USA) were used.
After the incubation with primary antibodies, a 10 minute
incubation with Biotinylated Goat Anti-polyvalent (Cat.
No. E-AB-1097; Elabscience) and a 10 minutes incubation
with Streptavidin – Horseradish Peroxide (HRP) (Cat. No.
434323; Thermo Fisher Scientific, Waltham, MA, USA)
were performed. Lastly, a mixture of 40 µL DAB Plus
Chromogen and 2 mL of DAB Plus substrate was applied
into tissue for 15 minutes. The expressions of ERβ and
IL-6 was manually counted in ten fields of view, using 400x
times magnification by two pathologists.
Determining Tumor Differentiation and Tumor
Infiltration
The percentage of immunoreactive tumor cells per 1000
cells was manually recorded. Tumor differentiation was
graded according to the World Health Organization (WHO)
2010 criteria, and tumor infiltration was defined based
on the American Joint Committee on Cancer (AJCC) 8th
edition.(17) For the statistical analysis purpose, in this
study, the tumor primer invasion was grouped into T1-T2
group, which were the tumor invasion into submucosa (T1)
and into muscularis propria (T2), as well as T3-T4 group,
which were the tumor invasion into subserous (T3) and into
peritoneum (T4).

Results

Clinical Characteristic of Samples
From the year of 2019, among 64 patients undergoing colon
resection in Dr. Soetomo General Hospital, 40 samples
fulfilled the inclusion and exclusion criteria. There was no
difference in the number of male and female patients (Table
1). The highest incidence of colorectal carcinoma was found
in patients in their 61-70 years old (13%), with a mean of
54.13±13.96. The youngest patient was 27 years old, while
the oldest was 78 years old.
Based on the microscopic tumor differentiation
analysis, 50% of the samples in this study were welldifferentiated, and the rest were moderate- and poordifferentiated (Table 1). The most tumor size was >5 cm
(60%), and in 57% of patients, the tumor had infiltrated

ERβ and IL-6 Expression in CRC Tumor Differentiation (Theodora I, et al.)
Indones Biomed J. 2024; 16(5): 481-6

into the peri colorectal tissues (T3). Interestingly, 45% of
the subjects have not had tumor metastases to the lymph
nodes. The evaluation results of ERβ IHC staining showed
an average of 35.5% of the colonic mucosal tissue were
carcinoma positive for ERβ and 70.86% were positive for
IL-6 (Table 1, Figure 1, Figure 2).
Tumor Differentiation was Correlated with ERβ
Expression
There was a significant difference between well-, moderate-,
and poor-differentiation based on the ERβ expression
(p=0.018), with better tumor differentiation (welldifferentiated) was associated with higher levels of positive
ERβ expression (37.96±9.43). In contrast, there was no
discernible difference between the well-, moderate-, and
poor-differentiation based in the IL-6 expression (p=0.486)
(Table 2).
Using the Spearman Correlation Test, the correlations
between ERβ expression and tumor differentiation was also
found to be significant (p=0.018). However, there were no
Table 1. The clinical characteristics pathological features of
samples (n=40).
Characteristic

Value

Gender, n (%)
Male
Female
Age (year), n (%)

20 (50)
20 (50)

21-30

1 (2.5)

31-40
41-50

4 (10)
8 (20)

51-60
61-70

10 (25)
13 (32.5)

71-80
Microscopic Differentiation, n (%)

4 (10)

Well-differentiated
Moderately differentiated
Poorly differentiated
Tumor Size (cm), n (%)

20 (50)
17 (42.5)
3 (7.5)

<3
3-5
>5
Tumor Infiltration, n (%)
T1 (limited to the submucosa)

4 (10)
12 (30)
24 (60)
1 (2.5)

T2 (through muscularis propria)
T3 (through muscularis propria into pericolorectal tissues)
T4 (through visceral peritoneum or other organs)
Metastases to Regional Lymph Node (N), n (%)

9 (22.5)
23 (57.5)
7 (17.5)

N0 (no regional lymph node metastases)
N1 (metastases in 1-3 regional lymph nodes)
N2 (metastases in >3 regional lymph nodes)
Expression per 1000 cells, mean±SD

18 (45)
14 (35)
8 (20)

ERβ

35.5±8.5

IL-6

70.86±14.1

483

The Indonesian Biomedical Journal, Vol.16, No.5, October 2024, p.397-486

Figure 1. Example of ERβ expression in mucous of CRC
subject. White arrows referred to positive ERβ expression in the
nucleus. Black bar: 10 µm.

correlations between ERβ expression and tumor infiltration
(p=0.836), as well as between ERβ expression and IL-6
expression (p=0.154) (Table 3). This results suggested
that the mechanism of tumor differentiation might indeed
involve the regulation of ERβ expression, but not IL-6.

Discussion

In this study the highest incidence of CRC cases was found
in patients aged 61-70 years old. The patient characteristics
obtained from this study did not differ much from the
characteristics of CRC patients at Sanglah Hospital, Bali,
where 59.5% of patients were male, and the most age group
was 50-60 years old.(18) However, the results of this study
showed that around 32% patients were under 50 years old,
with the youngest age was 27 years old. This was consistent
with earlier research showing an increase in early-onset
colorectal cancer (EOCRC) worldwide. Moreover, there
are 16% to 35% of EOCRC instances in individuals with
hereditary cancer diseases.(19,20)
In the current study, it was found that 75% of patients
are in the tumor infiltration stage that had penetrated the
serosa, or T3-T4 stage according to the Tumour, Node,
Metastasis (TNM) staging from the AJCC, and even 55%
had metastases to mesenteric lymph nodes either N1 (1-3
regional lymph nodes) or N2 (>4 regional lymph nodes),
indicating that the patient had entered at least stage IIIA17.
Furthermore, 60% of patients had tumors with a maximum
diameter of >5 cm. This demonstrates a lack of awareness
for carcinoma screening, and patients seek for clinical
help only after the obstruction symptoms developed. It has
been well known that the primary key to the successful
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treatment of colorectal cancer is the early detection of
malignancy, since no adjuvant therapy is needed in stage 1
patients. Even for the patients in stage 2, adjuvant therapy
is only needed in high-risk patients, including <12 lymph
nodes resected, poorly differentiated tumors, vascular or
lymphatic or perineural invasion, tumors with occlusion or
perforation, and those who are in the T4 infiltration stage.
(11) Interestingly, 45% of patients did not develop lymph
nodes metastases.
This study highlights the significance of ERβ
expression in CRC patients, particularly in Indonesia. The
f indings indicate that ERβ expression is inversely
correlated with tumor differentiation, suggesting that
increased ERβ expression is associated with better tumor
differentiation. This is consistent with previous studies that
have shown similar results in low-grade CRC, glial tumors,
and prostate adenocarcinoma.(5,21) Estrogen receptor had
a significant inverse correlation with tumor differentiation,
which suggests that increased ERβ expression leads to
better tumor differentiation. In accordance with our results,
another study also showed that ERβ expression was
considerably higher in low-grade CRC, which supports our
findings.(12) Furthermore, there is an inverse relationship
between ERβ and tumor grade in glial tumors (22) and
prostate adenocarcinoma (21). These findings suggest that
ERβ expression could be used to assess the prognosis for
CRC. Consequently, in order to validate the relationship
between ERβ expression and CRC patients’ survival
rate and disease progression, further cohort research is
required.
IL-6 is a pro-inflammatory cytokine that plays a
significant role in the tumor microenvironment.(23) High
IL-6 levels promote tumor growth, invasion, and metastasis.

Figure 2. Example of IL-6 expression in mucous of CRC
subject. White arrows referred to positive IL-6 expression in the
nucleus. White bar = 10 µm.

ERβ and IL-6 Expression in CRC Tumor Differentiation (Theodora I, et al.)
Indones Biomed J. 2024; 16(5): 481-6

DOI: 10.18585/inabj.v16i5.3324

Table 2. Comparison of ERβ and IL-6 expression within tumor differentiation.
Differentiation

ERβ Expression
(mean±SD)

Well

37.96±9.43

Moderate

32.51±6.8

Bad

32.47±0.93

IL-6 Expression
(mean±SD)

p- value

p- value

75.22±13.07
0.018*

64.91±13.49

0.486

88.20±7.99

Tested with Independent sample t-test. *p≤0.05 is considered to be significant.

It activates various signalling pathways, such as the Janus
kinase/signal transducers and activators of transcription
(JAK/STAT) pathway, which enhances cell proliferation and
survival.(24) IL-6 also contributes to an immunosuppressive
tumor microenvironment, that influence the differentiation
of immune cells. In this study, it was also found that IL-6
expression was high in poorly differentiated CRC. This result
is consistent with the report from previous study stating that
IL-6 expression was higher in poorly differentiated CRC
than well-differentiated CRC.(7) Elevated IL-6 levels in
CRC patients are associated with important implications
for tumor progression. The IL-6 signaling pathway plays
a critical role in promoting several malignant processes in
tumor cells, including cell cycle progression, proliferation,
anti-apoptotic mechanisms, metastasis, and angiogenesis.
(25) However, further cohort research with larger samples
might be necessary to be conducted to understand how IL-6
is correlated with these mechanisms.

Conclusion

The results of this study showed that there is statistically
significant correlation between tumor differentiation and
ERβ expression, wherein improved tumor differentiation
is linked to the higher levels of positive ERβ expression.
Although IL-6 expression was found to be high in poorly
differentiated CRC, but there was no discernible relationship
between IL-6 and tumor differentiation. These findings
suggest that while IL-6 was involved in the growth of the
tumor, ERβ expression might have an impact on tumor
differentiation.

Acknowledgments

Special thank to Departement of Pathology Anatomi Dr.
Soetomo General Hospital Indonesia for providing the
research samples. Thank you to dr. Diah, dr. Ety, dr. Willy
for their kind suggestion during the study discussion.

Authors Contribution

IT, IKS, VSB, and BDN were involved in the conception
and design of the study. IT, FE, YJH, and BDN analyzed and
interpreted the data. BDN performed the statistical analysis
of the daya. IT and BDN drafted the original article, as well
as revised the article for important intellectual content.
IT is responsible for obtaining the funding. VSB and IKS
supervised the study and gave final approval.

1.
2.

3.
4.

5.

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