Expression and clinical significance of CREB1 and CREB3 in gastric cancer and precancerous lesions

doi:10.21203/rs.3.rs-3343311/v1

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Expression and clinical significance of CREB1 and CREB3 in gastric cancer and precancerous lesions

https://doi.org/10.21203/rs.3.rs-3343311/v1

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Background: To investigate the expression and clinical significance of cyclic adenosine monophosphate responsive CREB1 and CREB3 in gastric cancer and precancerous lesions.

Methods and Results: All data was collected in June 2021 to April 2022 from the second affiliated hospital of Baotou medical college with archive wax block of 40 cases of chronic superficial gastritis. The expressions of CREB1 and CREB3 in different gastric tissues were detected by Western blot. Kaplan-meier Plotter was used to analyze the correlation between the expression of CREB1 and CREB3 and overall survival and progression-free survival of gastric cancer patients. The positions of CREB1 and CREB3 in the signaling pathway and their related upstream and downstream genes were analyzed using STRING database. (1) Immunohistochemistry staining results showed the positive expression rates of CREB1 and CREB3 in gastric cancer group significantly higher than those in chronic atrophic gastritis with intestinal metaplasia, but there was no significant difference between them and dysplasia group. Clinicopathological parameters analysis showed that the expression levels of both were correlated with depth of invasion, TNM stage, vascular invasion and lymph node metastasis. (2) Western blot results indicated that the protein expression of CREB1 and CREB3 increased successively in chronic superficial gastritis, chronic atrophic gastritis with intestinal metaplasia, and gastric cancer, and the difference was statistically significant.

Conclusion: CREB1 and CREB3 may be related to the occurrence, development and metastasis of gastric cancer, and the high expression of CREB1 and CREB3 may be related to the poor prognosis of gastric cancer patients.

Gastric cancer

CREB1

CREB3

Immunohistochemistry

Western blot

Gastric cancer is one of the common tumors that endanger human health around the world. In 2020, there were more than 1 million new gastric cancer cases and 769, 000 deaths worldwide (MM Cao et al. 2021), ranking the fifth in incidence and fourth in mortality globally (H Sung et al. 2021). The formation of gastric cancer is a multi-step and multi-factor process, and the currently recognized development process is: chronic superficial gastritis → chronic atrophic gastritis → gastric mucosal intestinal metaplasia → dysplasia → gastric cancer (P Correa et al. 2012). The key links in the evolution of gastric cancer are intestinal metaplasia and dysplasia of gastric mucosa, which have a high risk of carcinogenesis and are called pregastric cancer lesions. Cyclic adenosine monophosphate responsive element binding protein (CREB) is an intracellular transcription factor in eukaryotes, which can abnormally activate the transcription of tumor-related genes and promote the growth and metastasis of tumor cells. CREB is dephosphorylated and has no transcriptional activity in quiescent cells. When stimulated by downstream genes, such as proliferation, apoptosis, angiogenesis, metabolic abnormalities or the generation of tumor stem cells, CREB is phosphorylated, and many sites such as SER-133 are activated to regulate the transcription of target genes. CREB1 and CREB3, as their family members, have been confirmed to be involved in the development of a variety of tumors. Current studies have confirmed that CREB1 is highly expressed in esophageal cancer, colorectal cancer, lung cancer and other tumors, and CREB3 is related to the invasion and migration of breast cancer, colorectal cancer and thyroid cancer (SG Cheng et al. 2021; Y Cheng et al. 2020; R Zhang et al. 2021; BV Howley et al. 2017; PY Li. 2014; G Wang et al. 2021). In this study, the expression levels of CREB1 and CREB3 in gastric cancer and precancerous lesions were detected, and the relationship between the expression of CREB1 and CREB3 and the development of gastric cancer was explored, so as to provide theoretical basis and clinical diagnosis and treatment ideas for early diagnosis and molecular targeted therapy of gastric cancer.

Case data

A total of 170 gastric tissue samples were collected from the Department of Pathology, the Second Affiliated Hospital of Baotou Medical College from June 2021 to April 2022, including 40 cases of chronic superficial gastritis, aged 30–67 (49.15 ± 10.74) years. There were 40 cases of chronic atrophic gastritis with intestinal metaplasia, aged from 32 to 68 years (49.93 ± 10.48). There were 40 cases of dysplasia (including 16 cases of low-grade neoplasia and 24 cases of high-grade neoplasia), with an average age of (53.60 ± 11.37) years old ranging from 36 to 73 years old. Fifty patients with gastric cancer, aged 48–75 (61.78 ± 7.42) years, were all advanced gastric adenocarcinoma. There were 27 cases with moderate/high differentiation and 23 cases with low differentiation. There were 19 cases of stage I + II and 31 cases of stage III + IV. A total of 30 cases of chronic superficial gastritis, chronic atrophic gastritis with intestinal metaplasia, and gastric cancer were collected from fresh tissues during the same period. None of the enrolled patients received tumor-related therapy. The study was approved by the Medical Ethics Committee of our hospital.

Immunohistochemistry staining

Paraffin section dewaxing and hydration; EDTA solution was heated for antigen repair. After natural cooling, endogenous peroxidase blocker (Fuzhou MaiXin) was added and incubated for 10min at room temperature. After washing with PBS, non-specific staining blocker (Fuzhou MaiXin) was added, incubated for 10min, and primary antibody (Proteintech; CREB1 12208-1-AP 1:400, CREB3 11275-1-AP 1:200), refrigerator at 4℃ overnight; After rewarming and washing, biotin-labeled sheep anti-mouse/rabbit IgG polymer(Fuzhou MaiXin) was added by drop, incubated for 10min, streptomycillus anti-biotin protein-peroxidase (Fuzhou MaiXin) was added by drop after washing, and then DAB reagent was used for color development (Fuzhou MaiXin), and the slides were restained, dehydrated, transparent and sealed.

The results determine

CREB1 is mainly expressed in the nucleus and CREB3 is mainly expressed in the cytoplasm. Two senior pathologists read the films double-blind, and 5 unrepeated fields were randomly selected at high power to score. Scoring criteria: Staining intensity: 0 points for non-staining, 1 point for light yellow. Dark yellow counts 2 points, dark brown counts 3 points; Percentage of positive cell staining: 0 points for no staining, 1 point for<25%, 2 points for 26%-50%, 3 points for 51–75%, and 4 points for>75%; When the two scores were multiplied, the total score<6 was considered as low expression, and the total score ≥ 6 was considered as high expression.

Western blot

The tissue was lysed (Shanghai SG-C500053), centrifuged (12000g for 15min at 4℃), and the supernatant was taken for determination of BCA (Biosharp BL521A) protein concentration. Sds-page gel preparation (Biosharp BL565B), loading, electrophoresis (120V/20min); Transfer to PVDF membrane and block with rapid blocking solution for 5-15min at room temperature; Primary antibody was added and incubated overnight at 4℃. After washing with TBST for 3 times, HRP labeled secondary antibody was added, and the membrane was incubated at 37℃ for 1h. After washing with TBST for 3 times, ECL chemiluminescence was scanned and analyzed.

Kaplan-Meier plotter survival analysis

Kaplan-Meier plotter (http://kmplot.com/analysis/) is a based on the GEO, EGA and TCGA survival curve drawing database online tools, the largest database including breast cancer, ovarian cancer, lung cancer and stomach cancer. Kaplan-Meier plotter was used to analyze the correlation between the expression levels of CREB1 and CREB3 in gastric cancer and the prognosis of gastric cancer patients.

STRING database

STRING (https://string-db.org/) is an organism wide database of protein association networks designed to collect and integrate all known and predicted interactions between proteins, including physical and functional associations. We used STRING database to map the protein networks related to CREB1 and CREB3 and explore the association between CREB1 and other proteins.

Statistics

SPSS 20.0 statistical software was used to input and analyze the data of this experiment. The differences in immunohistochemical expression of CREB1 and CREB3 between groups and the association with clinicopathological parameters of gastric cancer were analyzed by chi-square test. The difference of protein expression between groups was analyzed by t test. P<0.05 was considered statistically significant.

Expression of CREB1 and CREB3 in gastric cancer and non-cancerous gastric tissues

The results of immunohistochemistry showed that the positive staining of CREB1 in different gastric mucosa was mainly located in the nucleus (Fig. 1), and the positive staining of CREB3 was mainly located in the cytoplasm (Fig. 2). The positive expression rates of CREB1 and CREB3 in gastric cancer, dysplasia and atrophic gastritis with intestinal metaplasia were significantly higher than those in chronic superficial gastritis (P<0.05). In addition, the positive expression rates of CREB1 and CREB3 in gastric cancer tissues were higher than those in chronic atrophic gastritis with intestinal metaplasia (P<0.05), but there was no significant difference between them and dysplasia group (P>0.05,Table 1).

Table 1

Expression of CREB1 and CREB3 in different gastric mucosal lesions
group	cases	CREB1			CREB3
group	cases	High expression	Low expression	Positive rate	High expression	Low expression	Positive rate
Chronic superficial gastritis	40	2	38	5%	4	36	10%
Chronic atrophic gastritis with intestinal metaplasia	40	8	32	20%	11	29	27.5%
hyperplasia	40	17	23	42.5%	19	21	47.5%
gastric carcinoma Total	50 170	24	26	48%	25	25	50%

Relationship between CREB1 and CREB3 expression and clinicopathological parameters in patients with gastric cancer

The expression levels of CREB1 and CREB3 in gastric cancer patients were correlated with the depth of tumor invasion, TNM stage, vascular invasion and lymph node metastasis, and the differences were statistically significant (P<0.05). There was no significant correlation with gender, age, tumor size and differentiation degree (P>0.05, Table 2).

Table 2

Relationship between CREB1 and CREB3 expression and clinicopathological parameters in patients with gastric cancer
Clinicopathological parameters	cases	CREB1		X²/P	CREB3		X²/P
Clinicopathological parameters	cases	High expression(n = 24)	Low expression(n = 26)	X²/P	High expression(n = 25)	Low expression(n = 25)	X²/P
Gender				0.278/0.598			0.739/0.390
male	29	13	16		13	16
female	21	11	10		12	9
Age				0.053/0.817			0.333/0.564
≤ 60	20	10	10		11	9
>60	30	14	16		14	16
Tumor size /cm				0.297/0.586			0.725/0.395
≤ 4	23	12	11		10	13
>4	27	12	15		15	12
Infiltrating depth				5.500/0.019			6.349/0.012
T1-T2	14	3	11		3	11
T3-T4	36	21	15		22	14
Lymph node metastasis				4.372/0.037			8.420/0.004
+	37	21	16		23	14
-	13	3	10		2	11
The degree of differentiation				0.001/0.982			0.725/0.395
low	23	11	12		10	13
high + medium	27	13	14		15	12
TNM staging				5.773/0.016			4.160/0.041
I + II	19	5	14		6	13
III + IV	31	19	12		19	12
Vascular invasion				3.978/0.046			8.013/0.005
+	26	16	10		18	8
-	24	8	16		7	17

The expressions of CREB1 and CREB3 in different gastric mucosal lesions were detected by Western blot

Western blot results showed that the protein expressions of CREB1 and CREB3 increased successively in chronic superficial gastritis, chronic atrophic gastritis with intestinal metaplasia, and gastric cancer, and the differences were statistically significant (P<0.01, Fig. 3).

Kaplan-Meier Plotter survival analysis of CREB1 and CREB3

Kaplan-Meier Plotter data showed high CREB1 expression were significantly lower than those with low CREB1 expression. Horizontal axis served as the overall survival time (Fig. 4, HR = 1.78, P<0.05) and progression-free survival time (Fig. 5, HR = 1.62, P<0.05) of gastric cancer patients. The overall survival time (Fig. 6, HR = 1.57, P<0.05) and progression-free survival time (Fig. 7, HR = 1.45, P<0.05) of gastric cancer patients with high CREB3 expression were also lower than those with low CREB3 expression.

CREB1 and CREB3 related gene protein network

Log in the STRING database, input the name of CREB1 protein, and the organism selects Homo sapiens to get the protein interaction network diagram (Fig. 8). It can be found that the proteins associated with it are as follows: CREBBP, EP300, RPS6KA5, MECP2, CRTC1, CRTC2, ATF2, JUN, TP53, TAF4, mainly play the role of phosphorylation-dependent transcription factors and participate in different cellular processes. The protein name of CREB3 was also input. As shown in Fig. 9, the related proteins included JUN, ATF4, CREBRF, DCSTAMP, CREB3L2, MBTPS1, MBTPS2, HCFC1, MYC, and NR0B2, which were mainly involved in cell proliferation and migration, as well as the expression of inflammatory genes.

Gastric cancer is one of the most common cancers in the world. At present, with the improving of people's living standard, the awareness of health examination is increasing day by day. However, the specificity of early symptoms of gastric cancer is low, and the degree of malignancy is high. Especially for advanced patients with metastatic potential, the long-term survival rate is still poor. Therefore, it is essential to comprehensively understand and explore the underlying mechanisms that promote the pathogenesis, progression and migration of gastric cancer, and to find novel biomarkers for clinical diagnosis and treatment. CAMP responsive element binding protein (CREB) is an intracellular transcription factor in eukaryotes. To investigate the expression of CREB1 and CREB3 in gastric cancer and precancerous tissues, and to provide help for the clinical diagnosis and treatment of gastric cancer.

CAMP responsive element binding protein 1(CREB1) is an important member of CREB family, and its coding gene is located in human chromosome 2q32-34. Studies have shown that CREB1 is involved in a variety of biological processes in human body. Due to the upregulation of CREB downstream target genes carrying CRE elements in their promoters mediated by CREB1 overexpression, it can stimulate tumorigenesis. At the same time, CREB1 overexpression is correlated with clinicopathological parameters of tumor patients. Including tumor stage, grade, metastasis, increased recurrence probability, poor prognosis and reduced survival rate. CAMP responsive element binding protein 3(CREB3) is a member of the CREB family and the prototype of CREB3 subfamily transcription factors. The family members of this subfamily include: CREB3, CREB3L1, CREB3L2, CREB3L3, CREBL4. CREB3 gene contains 8 introns and 9 exons and is located on chromosome 9 ^[8]. With the progress of research at home and abroad, CREB3 not only plays an important role in growth, development and metabolism, but also has been confirmed to be up-regulated in various malignant tumors.

Studies have found that the expression of CREB1 mRNA in adjacent normal tissues is significantly lower than that in esophageal cancer tissues, and its expression is related to TNM staging and lymph node metastasis, suggesting that CREB1 may be involved in the occurrence and development of esophageal cancer, and is related to the promotion of esophageal cancer cell proliferation, differentiation and migration (WM Deng et al. 2021). Jin (LG Jin. 2016) found that the expression of CREB1 in colorectal cancer was up-regulated compared with that in normal tissues, and was associated with poor prognosis of patients. In addition, the up-regulation of CREB1 expression has also been confirmed to be associated with lung cancer (HM Li et al. 2019), breast cancer (ZC Xin et al. 2020), liver cancer (M Zhu et al. 2022), prostate cancer (MJ Watson et al. 2021) ovarian cancer (CJ Li et al. 2021) and renal cell carcinoma (M Friedrich et al. 2020). CREB3 has been shown to be involved in various tumor biological processes. In colon cancer, Li (PY Li. 2014) found that the expression of CREB3 was correlated with the metastasis of colorectal cancer, and Kim (HC Kim et al. 2010) showed that the overexpression of CREB3 could promote the metastasis of metastatic breast cancer cells. In addition, CREB3 is also closely related to the growth, invasion and migration of thyroid cancer (G Wang et al. 2021), cervical cancer (H Kang et al. 2011) and lung cancer (HJ Yan et al. 2021).

Studies on CREB1 and gastric cancer showed that the expression of CREB1 in primary gastric cancer tissues and secondary lymph node metastases was gradually increased compared with non-neoplastic gastric mucosa by Wang, according to immunohistochemical analysis (YW Wang et al. 2015). Recent studies have also shown that CREB1 is highly expressed in gastric cancer tissues and cells, and a 5-year follow-up study has shown that patients with low CREB1 expression have a higher survival rate, and CREB1 is an independent risk factor for tumor size, tumor differentiation and invasion, suggesting that high expression of CREB1 is closely related to poor prognosis of patients found that knockdown of CREB1 could inhibit the growth of gastric cancer cells and induce cell apoptosis (X Huang et al. 2020; YJ Zhao et al. 2021). At present, there are few studies on CREB3 in gastric cancer. Some studies have found that CREB3 subfamily factor CREB3L3 may be correlated with the occurrence, development and prognosis of gastric cancer by using gene expression profiles of gastric cancer and adjacent tissues in TCGA database (BH Han. 2020). Still other group found that the expression of CREB3 regulator (CREBRF) was increased in primary gastric cancer tissues (J Han et al. 2018). This study found that the positive expression rates of CREB1 and CREB3 in gastric cancer, dysplasia, atrophic gastritis with intestinal metaplasia were significantly higher than those in chronic superficial gastritis (P<0.05). In addition, the positive expression rates of CREB1 and CREB3 in gastric cancer tissues were higher than those in chronic atrophic gastritis with intestinal metaplasia (P<0.05), suggesting that CREB1 and CREB3 may play an important role in the occurrence and development of gastric cancer. Clinicopathological parameters analysis showed that the protein expression level was correlated with the depth of invasion, TNM stage, vascular invasion and lymph node metastasis (P<0.05), suggesting that the two might enhance the ability of tumor invasion and metastasis. The results of Western blot showed that the protein expression of CREB1 and CREB3 increased successively in chronic superficial gastritis, chronic atrophic gastritis with intestinal metaplasia, and gastric cancer (P<0.01), suggesting again that CREB1 and CREB3 may promote the development of gastric mucosa carcinogenesis. In addition, Kaplan-Meier Plotter analysis showed that the overall survival time and progression-free survival time of gastric cancer patients with high expression of CREB1 and CREB3 were shortened, which may be related to the poor prognosis of gastric cancer patients. In this paper, the expression of CREB1 and CREB3 in gastric cancer was studied, but the biological mechanism and interaction between CREB1 and CREB3 in gastric cancer were not discussed. The upstream and downstream genes and proteins related to CREB1 and CREB3 were obtained through STRING database analysis, which may be helpful for the future exploration of their biological mechanism and specific molecular pathways.

In conclusion, the expression of CREB1 and CREB3 in gastric cancer tissues is increased, and the high expression of CREB1 and CREB3 may indicate the poor prognosis of gastric cancer patients, and may be used as biomarkers to predict the diagnosis, metastasis and prognosis of gastric cancer.

Ethical Approval :

This study and included experimental procedures were approved by Ethical Committee for Experiments of The second affiliated hospital of Baotou medical college (Approval NO. LW-004) in 9^th Feburary 2023. All experiments were approved by the , and performed in accordance with the Guidelines for Use of Animals in Experiments of Baotou medical college.

Competing of interest:

We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript . We have had no prior discussion with a Molecular Biology Reports Editorial Board Member about the work described in the manuscript.

Authors' contributions

Chi Wang: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials analysis data; Wrote the paper. Lixia Liu, Xiaoxia Li, Ruxue Kang, Qianru Ye, Hui Wang: Performed the experiments; Contributed reagents, materials, analysis tools or data. Xin yue: Contributed reagents, materials, analysis tools or data. Analyzed and interpreted the data. Jianyuan Chai: Conceived and designed the experi[1]ments; Wrote the paper.

Funding

Chi Wang was supported by National Health Commission of the People's Republic of China [202201440 (A)].

Availability of data and materials

All authors confirm that the data supporting the findings of this study are available within the article.

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No competing interests reported.

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Expression and clinical significance of CREB1 and CREB3 in gastric cancer and precancerous lesions

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Abstract

Figures

Introduction

Data and Methods

Case data

Immunohistochemistry staining

The results determine

Western blot

Kaplan-Meier plotter survival analysis

STRING database

Statistics

Results

Expression of CREB1 and CREB3 in gastric cancer and non-cancerous gastric tissues

Relationship between CREB1 and CREB3 expression and clinicopathological parameters in patients with gastric cancer

Kaplan-Meier Plotter survival analysis of CREB1 and CREB3

CREB1 and CREB3 related gene protein network

Discussion

Declarations

References

Additional Declarations

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