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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 9  |  Page : 311-318

Human epidermal growth factor receptor 2 expressions and Janus-activated kinase/signal transducer and activator of transcription 3-suppressor of cytokine signaling 3 pathway may be associated with clinicopathological features and prognosis of gastric cancer


1 Department of Oncology, Jining No. 1 People's Hospital, Jining 272011, P. R. China
2 Department of Gastrointestinal Surgery, Jining No. 1 People's Hospital, Jining 272011, P. R. China

Date of Web Publication29-Jun-2018

Correspondence Address:
Jingwei Fu
Department of Gastrointestinal Surgery, Jining No. 1 People's Hospital, No. 6 Jiankang Road, Jining 272011
P. R. China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.235348

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 > Abstract 

Objective: Our study aims to investigate the expression of human epidermal growth factor receptor 2 (HER-2), Janus-activated kinase/signal transducer, and activator of transcription 3-suppressor of cytokine signaling 3 (JAK/STAT3-SOCS3) pathway in gastric cancer (GC) and its relationship with clinicopathological features and prognosis of GC.
Materials and Methods: A total of 105 GC patients who underwent surgical resection were enrolled for our study, and corresponding 60 normal tissues adjacent to carcinoma (>10 cm from the carcinoma tissues) as control groups. Spearman correlation analysis was applied for correlation analysis among HER-2, STAT3, and SOCS3. Kaplan–Meier method and Cox proportional hazard model were applied for investigating the associations among HER-2, STAT3 and SOCS3 expressions and prognosis of GC patients.
Results: The expressions of HER-2 and STAT3 in GC tissues were increased, but SOCS3 expression showed an evident decrease with the change of depth of invasion, lymph node metastasis (LNM), and tumor node metastasis staging (all P < 0.05). The result of Spearman correlation analysis showed a positive correlation between HER-2 and STAT3 (r = 0.216, P < 0.05), while a negative correlation was observed between STAT3 and SOCS3 (r = –0.237, P < 0.05). Kaplan–Meier analysis results showed that the survival time of HER-2 and STAT3 negative group were both higher than their positive group (both P < 0.001), nevertheless, the survival time of SOCS3 negative group was lower than positive group (P < 0.001). Cox regression multivariate analysis indicated HER-2, STAT3, SOCS3, LNM, and depth of invasion were independent prognostic factors influenced the prognosis of GC (all P < 0.001).
Conclusion: Our study revealed that HER-2 may participates in the development, invasion and metastasis of GC by affecting the JAK/STAT3 pathway. HER-2, STAT3, and SOCS3 serve as reference indexes for the prognosis of GC patients.

Keywords: Gastric cancer, human epidermal growth factor receptor 2, prognosis, signal transducer and activator of transcription 3, signal transduction, signaling pathway, suppressor of cytokine signaling 3


How to cite this article:
Xu W, Fu J, Wu H, Sun W. Human epidermal growth factor receptor 2 expressions and Janus-activated kinase/signal transducer and activator of transcription 3-suppressor of cytokine signaling 3 pathway may be associated with clinicopathological features and prognosis of gastric cancer. J Can Res Ther 2018;14, Suppl S2:311-8

How to cite this URL:
Xu W, Fu J, Wu H, Sun W. Human epidermal growth factor receptor 2 expressions and Janus-activated kinase/signal transducer and activator of transcription 3-suppressor of cytokine signaling 3 pathway may be associated with clinicopathological features and prognosis of gastric cancer. J Can Res Ther [serial online] 2018 [cited 2019 Dec 6];14:311-8. Available from: http://www.cancerjournal.net/text.asp?2018/14/9/311/235348


 > Introduction Top


As cancer with a decrease in incidence all over the world, gastric cancer (GC) still remains the fourth most common cancer and the second leading cause of cancer-related death worldwide.[1],[2] The incidence and mortality of GC were proved with the regional difference that developing countries such as Eastern Asia, South America, and Eastern Europe had the highest incidence rates compared with economically developed countries.[3] According to estimates, more than 930,000 people suffer from GC and approximately 700,000 people die of it all over the world.[4] Symptoms of GC can be divided into two parts, which were presented as early symptoms and later symptoms, including loss of appetite, nausea, heartburn, upper abdominal pain, anemia, weight loss, difficulty swallowing, and blood-stained stool.[5] Tumor location, lymph node involvement, and depth of tumor invasion were proved to be the most significant clinicopathological prognostic factors.[6] Previous studies also revealed that interactions between environmental and genetic factors are closely associated in the etiology of GC, including helicobacter pylori infection, high salt consumption, iodine deficiency, cigarette smoking, alcohol consumption, human epidermal growth factor receptor 2 (HER-2), genetic instability, and DNA polymorphism.[7],[8]

HER-2 oncoprotein, also known as cerbB-2 protein, is 185-kDa transmembrane receptor tyrosine kinase that is a part of the four-member family of epidermal growth factor receptors, including HER-1 (also known as the EGFR), HER-3, and HER-4.[9] The tyrosine kinase activity of HER-2 intracellular domain induces signal transduction that plays crucial roles in cell proliferation, differentiation, and survival.[10] Signal transducer and activator of transcription (STAT) proteins, consist of seven proteins included STATs 1, 2, 3, 4, 5a, 5b, and 6, can regulate target genes transcription and transduce extracellular signals.[11] Of all the STAT members, STAT3 is the most intimately correlated with tumorigenesis and was first recognized as a DNA-binding factor binding to the interleukin-6 (IL-6)-responsive element selectively in 1994.[12],[13] Besides, the gene that encodes STAT3 is located on chromosome 17q21.[14] It is also reported that STAT3 is constitutively activated and overexpressed in many kinds of tumor, including leukemia, prostate cancer, breast cancer, multiple myeloma, and melanoma.[15],[16] While the last protein mentioned in our study is the suppressor of cytokine signaling 3 (SOCS3), one member of SOCS family, plays a pivotal role in regulating cellular responses downstream of the gp130 receptor.[17] SOCS3 has been proved to play crucial regulatory roles in cardiovascular diseases, such as heart failure, intravascular coagulation, and cardiovascular atherosclerosis; in addition, it is also reported that decreased SOCS3 expression play a big role in the occurrence of a malignant tumor.[18],[19] Although, a large amount of work has been performed revealing that HER-2, activated STAT3 and SOCS3 correlated with the development of GC, the underlying mechanism still remains less clear.[20],[21] For further investigating the underlying mechanism, we conducted this study to explore the expression of HER-2 and Janus-activated kinase/STAT3-SOCS3 (JAK/STAT3-SOCS3) pathway in GC and its relationship with clinicopathological and prognosis of GC.


 > Materials and Methods Top


Ethics statement

The study was carried out with the permission of the Institutional Review Board of Jining No. 1 People's Hospital. Written informed consents were obtained from all participants. Ethical approval for this study conformed to the standards of the Declaration of Helsinki.[22]

Study subjects

Between March 2004 and December 2008, 105 patients with the age range from 22 to 77 years (male/female: 69/36, median age: 48 years old [male/female: 62 years old/39 years old]) diagnosed with GC by pathologists undergoing operations at Jining No. 1 People's Hospital were selected as case groups and corresponding 60 normal tissues adjacent to carcinoma (>10 cm from the carcinoma tissues) as control groups. All patients underwent fibergastroscopy and were pathologically proved as GC, had no radiotherapy, chemotherapy, inflammation, and other complications before surgery. Besides, patients had no special medication history in the week before enrollment of this study, including proton pump inhibitor, H2 receptor antagonist, and so on. All patients were pathological diagnosed with GC by two pathologists at the same time, and no implication was found on normal tissues. The following information of patients were recorded: gender, age, occupation, family history, smoking status, conditions of high salt, cardinal symptom, operation time, the location of tumor, depth of invasive, degree of differentiation, conditions of transfer, and methods of operation. According to the standard of World Health Organization,[23] the smoker was the one who smoked for more than 1 year (a cigarette per day) and the person drank more than 200 mg was regarded as intemperate. Questionnaire survey or/and reexamination of gastroscope was conducted for the follow-up to record the survival time or cause of death. Patients were followed up for 1–80 months with the median follow-up time of 30 months. Clinical observation was closely applied for 105 GC patients, including gastroscopy, chest, and abdomen CT imaging.

According to the seventh edition of tumor node metastasis (TNM) staging criteria of GC issued by the American Joint Committee on Cancer in 2010:[24] 21 cases in stage I, 25 cases in stage II, 28 cases in stage III, and 31 cases in stage IV; lymphatic metastasis in 55 cases, not lymphatic metastasis in 50 cases. On the basis of the degree of differentiation, GC patients were divided into two groups: Higher and middle differentiation group (n = 44) and lower differentiation group (n = 61).

Sample processing

All samples were fixed immediately in 10% formalin after surgical resection, dehydrated step by step and embedded by petrolin. After the above step, samples were cut into slices with 4 μm for hematoxylin-eosin staining and immunohistochemistry (IHC).

Immunohistochemistry

Mouse anti-human HER-2 antibody and rabbit anti-human STAT3, SOCS3 polyclonal antibody were bought from Beijing Zhongshan Golden Bridge biological Co., Ltd., and Boster biological engineering Co., Ltd., respectively. Besides, IHC streptavidin-perosidase (SP) kit (instant type) and diaminobenzidine staining kit were bought from Beijing Zhongshan biological products Co., Ltd. Further procedures were performed using SP IHC kit according to the manufacturer's instructions, positive control was provided by company supplied reagent, and phosphate buffered saline was set as negative control to replace primary antibody.

[Table 1] shows the scoring standard of immunohistochemical staining result of HER-2, STAT3 and SOCS3. HER-2 can be seen positive expression by the occurrence of tan particles in cytomembrane or cytolymph, STAT3 was tan particles in cytolymph, while SOCS3 was tan particles in nucleus.[25] All staining results were approved by two experienced pathologist.
Table 1: Scoring standard of immunohistochemical staining result of HER-2, STAT3 and SOCS3

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Statistical analysis

SPSS 21.0 software (SPSS, Inc., Chicago, IL, USA) was applied for statistical analysis. The categorical data was analyzed by rank-sum test and χ 2 test, and Spearman correlation analysis was applied for correlation analysis. Survival analysis was performed using Kaplan–Meier method, and multivariate analysis was carried out with the utilization of the Cox proportional hazard model. All tests are two-tailed test and a P < 0.05 presented as a significant difference.


 > Results Top


Immunohistochemistry results of human epidermal growth factor receptor 2, signal transducer and activator of transcription 3 and suppressor of cytokine signaling 3

Expressions of HER-2, STAT3, and SOCS3 can be seen in both cytolymph and nucleus, and mainly presented cytoplasmic type, and tan or sepia granules. Positive expressions of HER-2 and STAT3 in normal tissues were lower compared to those in GC tissues while positive expression of SOCS3 in normal tissues were higher compared to those in GC tissues [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d, [Figure 1]e, [Figure 1]f.
Figure 1: Immunohistochemistry results of human epidermal growth factor receptor 2, signal transducer and activator of transcription 3 and suppressor of cytokine signaling 3 (a) human epidermal growth factor receptor 2 negative expression in normal gastric tissues; (b) human epidermal growth factor receptor 2 positive expression in gastric cancer; (c) signal transducer and activator of transcription 3 negative expression in normal gastric tissues; (d) signal transducer and activator of transcription 3 positive expression in gastric cancer; (e) suppressor of cytokine signaling 3 positive expression in normal gastric tissues; (f) suppressor of cytokine signaling 3 negative expression in gastric cancer

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Expressions of human epidermal growth factor receptor 2 in gastric cancer and normal tissues, and associations between human epidermal growth factor receptor 2 expression and clinicopathological features of gastric cancer

Compared with control group, positive expression rate of HER-2 in GC tissues presented a significantly increased trend (69.5% vs. 36.7%, P < 0.05). In different clinical features, the expression of HER-2 was significant difference in the following groups: with or without family history; drinking history; high, middle, and low differentiation group; with or without lymph node metastasis (LNM), I/II and III/IV TNM staging; and depth of invasion (T1 + T2 and T3 + T4) (all P < 0.05), while no such difference was observed in sex, age, smoking conditions, and high salted food (all P > 0.05) [Table 2] and [Table 3].
Table 2: The expressions of HER-2 in normal and gastric cancer tissue

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Table 3: The expression of HER-2 in different clinicopathologic features of gastric cancer tissues

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Expressions of signal transducer and activator of transcription 3 in gastric cancer and normal tissues

STAT3 presented an evidently increased positive expression rate in GC tissues compared to control group (71.4% vs. 13.3%, P < 0.05). As for all different clinical features, a significant difference of STAT3 protein expression was found in groups included with or without family history; drinking history; high, middle and low differentiation group; with or without LNM, I/II and III/IV TNM staging; and depth of invasion (T1 + T2 and T3 + T4) (all P < 0.05); nevertheless, there was no significant difference in STAT3 expression was observed in sex, age, smoking conditions, and high salted food (all P > 0.05) [Table 4] and [Table 5].
Table 4: The expression of STAT3 in normal and gastric cancer tissues

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Table 5: The expression of STAT3 in different clinicopathologic features of gastric cancer tissues

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Expressions of suppressor of cytokine signaling 3 in gastric cancer and normal tissues

We found a decreasing positive expression rate of SOCS3 in GC tissues compared with the control group (28.5% vs. 91.6%, P < 0.05). The expression of SOCS3 was related to family history, drinking history, differentiation, LNM and TNM staging, and depth of invasion (all P < 0.05), while other clinical factors such as sex, age, smoking conditions, and high salted food were not associated with SOCS3 expression (all P > 0.05) [Table 6] and [Table 7].
Table 6: The expression of SOCS3 in normal and gastric cancer tissues

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Table 7: The expression of SOCS3 in different clinicopathologic features of gastric cancer tissue

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Correlations between human epidermal growth factor receptor 2, signal transducer and activator of transcription 3 and suppressor of cytokine signaling 3 in gastric cancer

We used Spearman correlation analysis to analyze the expressions of HER-2 and STAT3 in GC under IHC. The result of Spearman correlation analysis showed a positive correlation between HER-2 and STAT3 (r = 0.216, P < 0.05) [Table 8], while a negative correlation was observed between STAT3 and SOCS3 (r = −0.237, P < 0.05) [Table 9].
Table 8: Correlations between HER-2 and STAT3 in gastric cancer

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Table 9: Correlations between STAT3 and SOCS3 in gastric cancer

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Association between the expressions of human epidermal growth factor receptor 2, signal transducer and activator of transcription 3, suppressor of cytokine signaling 3 and survival time

The results of Kaplan–Meier survival curve showed that all 105 patients received follow-up had the median survival time of 30.000 months, and the 5 years survival rate of these GC patients were 30.5%. Among the total survival time, “−” and “+–+++” group of HER-2 expression presented survival time of 66.000 and 24.000 months, respectively, the STAT3 expression of these two groups showed survival time of 65.500 and 21.000 months independently, while the expression of SOCS3 emerged a survival time of 23.000 and 63.000 months severally. Besides, the survival time of HER-2 and STAT3 negative group were both higher than their positive group (HER-2: χ 2 = 14.424, P = 0.000; STAT3: χ 2 = 19.919, P = 0.000) [Figure 2]a and [Figure 2]b; nevertheless, the survival time of SOCS3 negative group was lower than positive group (χ 2 = 20.571, P = 0.000) [Figure 2]c.
Figure 2: Kaplan–Meier survival curve showed the correlation of the expression levels of human epidermal growth factor receptor 2, signal transducer and activator of transcription 3 and suppressor of cytokine signaling 3 and survival of gastric cancer patients (a) the expression levels of human epidermal growth factor receptor 2; (b) the expression levels of signal transducer and activator of transcription 3; (c) the expression levels of suppressor of cytokine signaling 3

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Multivariate analysis of factors influenced prognosis of gastric cancer

Univariate analysis verified associations between HER-2, activated STAT3, SOCS3, LNM, depth of invasion, degree of differentiation, TNM staging, and prognosis of GC. After Cox regression multivariate analysis, we found that HER-2, STAT3, SOCS3, LNM, and depth of invasion were independent prognostic factors influencing the prognosis of GC (all P < 0.05) [Table 10].
Table 10: Multivariate analysis of factors influencing prognosis in gastric carcinoma

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 > Discussion Top


The present study was undertaken to investigate the HER-2 expressions and JAK/STAT3-SOCS3 pathway in GC and its relationship with clinicopathological and prognosis of GC. Our study demonstrated that HER-2, activated STAT3 and SOCS3 participated in the development, invasion, and metastasis of GC, and HER-2, STAT3, and SOCS3 can serve as reference indexes for the prognosis of GC patients.

Cancer is deemed as a genetic disease with abnormities occurred in both the genome and accumulation of epigenome, sufficing cells to escape from normal regulatory controls by the exposure to exogenous and endogenous damaging agents.[26] Alterations to the JAK/STAT pathway are identified in numerous cancers, including GC, breast cancer, and so on.[27] JAK/STAT pathway plays a crucial role in cell proliferation and differentiation which contained with many receptors, including JAK family, STATs family, T and B lymphocytes antigen receptor.[28],[29] SOCS family is downstream molecules of STATs, which mainly play an inhibition role in abnormal activation of JAK/STAT pathway, and the most important member of SOCS, SOCS1, and SOCS3, are the most potential inhibitory factors.[30],[31] Previous study also found a negative correlation between SOCS3 and STAT3, which was in accord with our result.[32] Besides, it is also reported that the activation of the JAK/STAT pathway is essential for HER-2 mediated transformation, and HER-2 may influence JAK/STAT pathway to result in the development of GC.[33] Furthermore, our study also revealed that positive expression rate of HER-2 in GC tissues presented a significantly increased trend compared with the control group. It is reported that the overexpression of HER-2in GC was first depicted in 1986 by IHC.[34] Consistent with our results, previous studies also suggested a higher positive expression of HER-2 in GC tissues compared with normal tissues.[34],[35]

In the physiological condition, STAT3 can be activated by many factors, including JAK, EGFR, IL-6, growth factor receptors and oncoprotein, and then participated in cell proliferation, differentiation, survival, apoptosis, transformation, and immunity.[36] However, the overexpression of sustained activation of STAT3 was found in many common malignancies, which may promote the development of malignancies, such as hepatocellular carcinoma.[37] In our study, STAT3 presented an evidently increased positive expression rate in GC tissues compared to control group, and expression of SOCS3 was related to family history; drinking history; high, middle, and low differentiation group; LNM and TNM staging; and depth of invasion. A study conducted by Kim et al. also clarified that LNM and TNM staging and depth of invasion were evidently related to STAT3 positivity, and GC tissues had higher positive expression rate of STAT3.[38]

Finally, our follow-up results also showed that the survival time of HER-2 and STAT3 negative group were both higher than their positive group; nevertheless, the survival time of SOCS3 negative group was lower than the positive group. Lower et al. demonstrated that the expression of HER-2 in the tumor may decide the grade malignancy of the tumor while a lower expression may correlate with lower abilities of proliferation, invasion, and metastasis of the tumor.[39] Besides, the higher expression was proved to be correlated with the occurrence and development of malignancies, and it was also found in GC tissues resulting in lower survival time.[40],[41] Furthermore, the decrease or deficiency of SOCS3, mainly caused by promoter region methylation of DNA, was deemed to as one of the most important factors in resulting in malignancies, including GC.[42],[43]

To sum up, our present study demonstrated that HER-2, activated STAT3, and SOCS3 participated in the development, invasion, and metastasis of GC, and they can serve as reference indexes for the prognosis of GC patients. However, it should be noted that due to the limited sample size of our study, this conclusion needs to be further investigated and confirmed.

Acknowledgments

We would like to give our sincere appreciation to the reviewers for their helpful comments on this article.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]



 

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