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Year : 2019  |  Volume : 62  |  Issue : 4  |  Page : 549-555
Loss of c-Cbl expression correlates with de-differentiation status and lymphatic metastasis in gastric cancer

1 School of Life Sciences, University of Science and Technology of China, Hefei, Anhui; Jiangsu Key Lab of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
2 Department of Pathology, The People's Hospital of Suzhou National Hi-Tech District, Suzhou, China
3 Department of General Surgery, Affiliated Hospital of Jiangnan University, Wuxi, China
4 Jiangsu Key Lab of Medical Optics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China

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Date of Web Publication14-Oct-2019


Context: C-Cbl is an important negative regulator of the cell signaling that acts as an adaptor protein and E3 ubiquitin ligase. The role of c-Cbl in development and regulation of human cancer has aroused intensive attention. Aims: In this study, we aimed to assess the correlation between the expression of c-Cbl and clinicopathological parameters and explored the role of c-Cbl in the development and progression of GC. Settings and Design: This is a Pilot study. Methods and Materials: In total, 84 tissue samples including 44 gastric cancers (GC) and 40 matched adjacent normal tissues were collected after surgery. Then tissue microarray (TMA) and immunohistochemistry (IHC) technology were combined to detect the protein expression of c-Cbl. Statistical Analysis Used: Statistical analysis was performed using SPSS 22.0 (IBM Corporation, Armonk, NY, USA). Results: We have studied the correlation between c-Cbl expression and clinicopathological parameters. Our study showed that c-Cbl has a low expression in 61.4% (27/44) of GC tissues, and the incidence of cases was significantly higher than that in adjacent normal tissues (P < 0.0001). In addition, the correlation between c-Cbl expression and gastric carcinoma subtype (P = 0.027), histological type (P = 0.033), Borrmann classification (P = 0.009), histological differentiation (P = 0.0005), lymph node metastasis (P = 0.007), and intravascular tumor thrombus (P = 0.036) has also been revealed. Conclusions: Our results show that c-Cbl is down-regulated in GC tissues compared with normal gastric tissue, which may play an important role in the development and progression of GC.

Keywords: c-Cbl, de-differentiation, gastric cancer, lymph node metastasis, negative regulator

How to cite this article:
Chen C, Hui Y, Chen Y, Qian C, Sun M. Loss of c-Cbl expression correlates with de-differentiation status and lymphatic metastasis in gastric cancer. Indian J Pathol Microbiol 2019;62:549-55

How to cite this URL:
Chen C, Hui Y, Chen Y, Qian C, Sun M. Loss of c-Cbl expression correlates with de-differentiation status and lymphatic metastasis in gastric cancer. Indian J Pathol Microbiol [serial online] 2019 [cited 2023 Dec 1];62:549-55. Available from:

   Introduction Top

Gastric cancer (GC) is the fourth most frequent cancer, with a high incidence and mortality rate.[1] Worldwide, about 738,000 people die because of stomach cancer each year, and 70% of these cases occur in developing countries. More than one-third of GC cases occur in China.[2] In addition, the prognosis of patients with GC is poor, and the overall five-year survival rate of patients is less than 35%.[3] This is often caused by a variety of factors, including late diagnosis, delayed treatment, chemotherapy resistance, and cancer recurrence.[4] Therefore, new diagnostic and therapeutic targets will contribute in better survival rate and understanding of pathological mechanisms.

C-Cbl is a 120 kDa cytoplasmic protein that functions both as a multivalent adaptor and an E3 ubiquitin-protein ligase in tyrosine kinase signaling pathways, involved in many cell types.[5],[6] c-Cbl harness the expression or activation of protein tyrosine kinases by ubiquitination, internalization, and lysosome/proteasome degradation, leading to negative regulation of signal transduction and directing lysosome degradation.[7] Protein tyrosine kinases act as molecular switch to control variety of cellular signals, and their malfunction lead to various human malignancies. In this context, c-Cbl may play an important role as a tumor suppressor in pathogenesis of human cancer. Moreover, the c-Cbl-dependent negative regulation is considered to have a role in tumorigenesis.[8] It has been proved that loss of c-Cbl protein in GC is dependent on Met kinase activity.[9],[10],[11],[12]

Defects in c-Cbl protein have been proved to be associated with malignancy and immune dysfunction.[7] Studies have shown that mutant c-Cbl promoted the development of medullary malignancy through persistent intracellular signal transduction and proliferation of hematopoietic stem cell.[13],[14],[15] Certain some evidences suggest that the destruction of c-Cbl function may lead to the pathogenesis of other solid tumors.[16],[17],[18],[19],[20] Lai et al. (2012) reported the expression of c-Cbl in GC and found the relationship between loss of c-Cbl and deregulation of EGFR signaling pathway,[12] but few studies are undertaken to evaluate clinical importance of c-Cbl.

In this study, we examined the expression of c-Cbl in 44 GC tissues using immunohistochemistry (IHC) and tissue microarray (TMA) technology and compared it with the expression in adjacent normal tissue. We also evaluated the correlation between the expression of c-Cbl and clinicopathological parameters and explored the role of c-Cbl in the development and progression of GC.

   Subjects and Methods Top

Patients and tissue samples

All tissue blocks were obtained randomly from the Department of General Surgery, local Affiliated University Hospital from October 2017 to April 2018. All the 44 patients were treatment naïve before surgery. The 40 adjacent normal tissues were obtained from gastrectomy (>5 cm). All samples were clinically evaluated and confirmed by two independent pathologists. Median age of cancer patients was 65 years (range: 53 to 82 years). The type of GC tumors was classified according to the World Health Organization (WHO) histological classification of GC in 2002 and Lauren classification.[21],[22] The final stage of samples was confirmed according to the International Cancer Control League (UICC) classification system.[23] Clinicopathological characteristics of the patients are summarized in [Table 1]. All tissue samples were obtained after informed written consent of patients, and the research protocol was approved by the Human Research Ethics Committee of the local University Affiliated Hospital.
Table 1: Association of high expression of c-Cbl with clinicopathological characteristics in gastric cancer patients

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Construction of tissue microarray

The tissue microarrays were created from resected GC samples from the Jiangnan University Affiliated Hospital. The samples were fixed (using 10% formalin solution) and cut into tissue specimens. Hematoxylin and eosin (H and E) staining were employed to select the tumor area and adjacent normal area. Then the corresponding part on the donor wax block was selected as the material selection site according to the mark on the H and E slice. A cylindrical spotting tissue with a diameter of 2.0 mm was dug using a TMA instrument, and placed into the acceptor wax block from top to bottom in a left-to-right order. A total of 84 gastric tissues (including 44 GC tissues and 40 adjacent normal tissues) were included in the array block. Adequate cases are defined as more than 10% of the core area occupied by the tumor. A 5 μm thick sections were cut continuously from the receptor block and transferred to a poly-L-lysine coated glass slide. H and E staining was performed on the TMA to confirm the tumor tissue.

Immunohistochemical staining

The expression level of c-Cbl protein in TMA was determined by IHC. In short, the tissue sections were dewaxed in xylene and rehydrated through gradient ethanol. Tissue sections were heated in Tris-EDTA antigenic recovery buffer (pH 8.0) for 15 minutes in a microwave oven. After cooling naturally, tissue sections were then treated with 3% H2O2 for 10 minutes to block endogenous peroxidase activity. Tissue sections were blocked with 2% bovine serum albumin (Catalog No. A8020; Solarbio) and incubated with c-Cbl antibody (LS C358440, 1:50) at 4°C for overnight. Staining for c-Cbl in TMA was carried out using the Envision kit (Dako; EnVision Detection Systems). After PBS washes again, sections were incubated with secondary antibody and stained with the 3,3'diaminobenzidine reagent. Finally, the tissue sections were counterstained with hematoxylin, dehydrated with graded alcohol, cleared in xylene, and mounted with permanent mounting media.

C-Cbl expression analysis

C-Cbl expression was scored using a semi-quantitative H-score, which simultaneously measure the intensity of staining and the percentage of positive stained cells at that intensity. The immunostaining intensity was evaluated using a numeric score ranging from 0 to 3, reflecting the intensity as follows: 0, no staining; 1, weak staining (light yellow); 2, moderate staining (brown yellow); and 3, intense staining (tan). The expression range was scored as follows: <20% (0 points), 20% to 50% (1 point), 51% to 75% (2 points), and >75% (3 points). The value from dye intensity was then multiplied by the value of the expression range to obtain the overall score. ≤2 points, low expression and >2 points, high expression. Statistical analysis was performed using SPSS 22.0 (IBM Corporation, Armonk, NY, USA), and the relationships between c-Cbl expression and clinicopathological variables were examined using the Chi-square test. P≤ 0.05 was considered to indicate statistical significance.

   Results Top

Expression of c-Cbl is reduced in GC tissues compared with adjacent normal tissues

IHC was performed on TMA from 44 GC tissues and 40 matched tumor adjacent normal tissues. c-Cbl protein was mainly expressed in the cytoplasm, and the degree of coloration varies from tan to brown [Figure 1]a. Quantification of IHC in TMA showed that the expression of c-Cbl in GC tissues (17/44, 38.6%) was significantly lower than in adjacent normal tissues (35/40, 87.5%) (P < 0.0001) [Figure 1]b and [Table 2].
Figure 1: C-Cbl expression in gastric cancer tissues and adjacent normal tissues. (a) IHC of c-Cbl in gastric cancer tissues and adjacent normal tissues. Tumor samples were layered into c-CblLow and c-CblHigh groups and representative images are displayed. Scale bar, 20 μm. (b) Quantification of c-Cbl expression in gastric cancer tissues and adjacent normal tissues (P < 0.0001)

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Table 2: C-Cbl expression in gastric cancer and adjacent normal tissue

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C-Cbl down-regulation correlates with de-differentiation phenotype of GC

The tumor differentiation stage is a core aspect of the clinicopathological classification of solid malignancies. Tumors with a low degree of differentiation are generally more malignant and aggressive than tumors with a high degree of differentiation.[24] To examine whether the expression level of c-Cbl protein is related to the degree of differentiation of GC, we compared the expression value of c-Cbl in GC tissues with different degrees of differentiation. About 78.6% (11/14) moderately differentiated tissues showed strong staining for c-Cbl, while a smaller fraction of poorly differentiated (7/30, 23.3%) showed positive staining [Figure 2]a and [Figure 2]b. Compared with moderately differentiated GC tissues, c-Cbl expression was significantly reduced in poorly differentiated GC tissues with higher tumor malignancy (P < 0.0001) [Figure 2]b.
Figure 2: C-Cbl expression in differentiated and poorly differentiated tissues in gastric cancer. (a) IHC of c-Cbl in differentiated tissues and poorly differentiated tissues of gastric cancer. Tumor samples were layered into c-CblLow and c-CblHigh groups and representative images were displayed. Scale bar, 20 μm. (b) Quantification of c-Cbl expression in differentiated and poorly differentiated tissues of gastric cancer (P = 0.0005)

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GC samples with low c-Cbl expression show high degree of lymph node metastasis

Similar to other malignant tumors, tumor invasion and metastasis are the direct cause of death in patients with GC.[25] When GC grows into a solid malignant lesion, the invasiveness is significantly increased and prone to metastasis. The proportion of c-Cbl Low expression increased with the degree of lymph node metastasis (PN0 = 7/12, 58.3%; PN2 = 11/17, 64.7%: PN3 = 7/7,100%) [Table 1], except for PN1 tissues. These results suggest that c-Cbl Low expression is associated with lymph node metastasis (P = 0.007) [Figure 3]a and [Figure 3]b.
Figure 3: C-Cbl expression in different degrees of lymph node metastasis. (a) IHC of c-Cbl in GCs with different degrees of lymph node metastasis. Tumor samples are layered into c-CblLow and c-CblHigh groups and representative images are displayed. Scale bar, 20 μm. (b) Quantification of c-Cbl expression in different degrees of lymph node metastasis in gastric cancer (P = 0.007)

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Expression levels of c-Cbl are associated with the histopathological characteristics of GC

To determine whether c-Cbl is important in determining the clinical outcome of GC patients, we next examined the relationships between c-Cbl expression and histopathological characteristics of these patients. [Table 1] shows the correlation between expression of c-Cbl and clinicopathological features of GC patients. In our study, clinical GC samples were divided into three groups including tubular (29/44), mucinous (5/44), and mixed carcinoma (10/44), and we found that c-Cbl was differentially expressed in different histological type of GC (P = 0.033) [Figure 4]a, especially tubular adenocarcinoma. Simultaneously, low expression of c-Cbl is also highly associated with gastric carcinoma subtype (P = 0.027) [Figure 4]b, Borrmann classification (P = 0.009) [Figure 4]c, and intravascular tumor thrombus (P = 0.036) [Figure 4]d, independent of other histopathological characteristics.
Figure 4: Correlation of c-Cbl expression with histopathological characteristics. TMA analysis of gastric cancer showed that low expression of c-Cbl was correlated with (a) Histological type; (b) Gastric carcinoma subtype; (c) Borrmann classification; (d) Intravascular tumor thrombus. *P < 0.05, **P < 0.01

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   Discussion Top

The depletion of c-Cbl expression increases tyrosine kinases sensitivity, and release other targets, such as epidermal growth factor receptor (EGFR).[5],[26],[27] Thereby, the loss of c-Cbl-dependent negative regulation is recognized as a mechanism that contributes to tumorigenesis and development of GC.[12],[28],[29] In this study, we aimed to assess the c-Cbl protein expression in GC patients and excavated the correlation between c-Cbl expression and clinicopathological parameters. We applied TMA and IHC to detect the expression of c-Cbl in 44 GC tissues and 40 matched adjacent normal tissues. The expression of c-Cbl in GC tissues was lower compared to adjacent normal tissues, while the expression in moderate differentiated cancer and early disease was higher than in poorly differentiated cancer and advanced disease.

The c-Cbl mutation has been reported to down-regulate EGFR signaling and reduce cell proliferation and migration in breast cancer cell lines.[28] These studies confirmed the role of c-Cbl in negative regulation of receptor tyrosine kinase (RTK), indicating that it may be a tumor suppressor. Strict regulation of signaling by RTKs is essential for normal biological processes, whereas disruption of this regulation can lead to tumor initiation and progress.[30],[31] The results of this study indicate that c-Cbl down-regulation may be related to GC tumorigenesis. In addition, tumor differentiation is closely related to malignant tumors, well-differentiated cells are usually relatively less malignant.[32] We have found that the expression of c-Cbl is also associated with the degree of differentiation. The expression of c-Cbl is increased with the degree of differentiation of GC tissue, which suggested that c-Cbl may be associated with suppression of GC. The high expression of c-Cbl at early stages decreased the progression of GC, indicating that c-Cbl has a protective role in tumor progression to a certain extent.

Histopathological analysis revealed that low c-Cbl expression was associated with gastric carcinoma subtype, histological type, Borrmann classification, histological differentiation, lymph node metastasis, and intravascular tumor thrombus. Further, we have shown that the tissues with high degree of lymph node metastasis tend to have low c-Cbl expression. c-Cbl may down-regulate signaling molecules, limiting the migration and invasion of tumor cells, leading to decreased motility of cancer cells.[33] These results may partially explain the high rate of lymphatic invasion and metastasis in gastric cancer tissues with low c-Cbl expression. Consistently, c-Cbl has been demonstrated to inhibit cell migration activity in melanoma,[34] breast cancer,[35] and glioma cells.[33] It should be noted that, although the proportion of tumors with low c-Cbl expression increased with the degree of lymph node metastasis, showing a high frequency of low c-Cbl expression in patients with lymph node metastasis. Based on the current findings, we hypothesized that down-regulation of c-Cbl may be involved in the progression of GC by reversing the aggressive phenotype of cancer cells. However, the c-Cbl protein expression was low in PN1 GC, which showed the contrary results. Unknown regulatory mechanisms may be involved in the translation process that needs to be explored.

To further elucidate the role of c-Cbl protein in progression of GC, we tested whether the expression of c-Cbl is related to histopathological features. We found that c-Cbl protein expression was negatively correlated with histological type of gastric cancer, GC subtype, Borrmann classification, and intravascular tumor thrombosis. Consistent to our findings, c-Cbl expression was lower than adjacent normal tissues of the skull base chordoma and negatively associated with OS in patients with colorectal cancer.[36] It has also been observed that knockout of c-Cbl promoted proliferation, migration and invasion of breast cancer cell lines MCF-7 and MDA-MB-231 cells.[35] Furthermore, c-Cbl-mediated ubiquitination leads to down-regulation of EGFR to promote tumor initiation and progression in colorectal cancer.[37] Suzue et al. (2006) also reported that c-Cbl promotes ubiquitination and degradation of insulin-like growth factor receptor (IGFR) in osteoblasts during osteoblast differentiation to inhibit bone formation.[38] Clearly, c-Cbl participates in the growth, invasion and metastasis of GC through ubiquitination, and degradation of many signaling proteins in the intracellular signaling pathway. Therefore, certain drugs that enhance the activity of c-Cbl may provide new strategies for cancer therapy.[10],[39],[40] Ma et al. (2016) revealed a novel mechanism that c-Cbl plays an important role in HER2 degradation enhanced by JWA in GC cells. Knockdown of c-Cbl rescued JWA-induced HER2 down-regulation and lapatinib resistance, so low levels of c-Cbl may be predictive markers of lapatinib sensitivity, patients with c-Cbl low expression may benefit from such lapatinib treatment in human GC.[41]

In conclusion, the down-regulation of c-Cbl may play an important inhibitory role in the malignant transformation of gastric cancer cells and is negatively correlated with growth, invasion, and metastasis of gastric cancer. Thus, c-Cbl can be considered as a promising marker for invasive behavior of gastric cancer. Our results also suggest that c-Cbl can be used as a potential basis for future treatment of gastric cancer; however, the underlying mechanisms of c-Cbl in GC need further investigation.

Financial support and sponsorship

This work was supported by the National Natural Science Foundation of China (61675226) and Hundred-Talent Program of Chinese Academy of Sciences.

Conflicts of interest

There are no conflicts of interest.

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Correspondence Address:
Chengjia Qian
Department of General Surgery, Affiliated Hospital of Jiangnan University, Huihe Road 200, Wuxi, 214062
Minxuan Sun
Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, No. 88 Keling Road, Huqiu District, Suzhou, Jiangsu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_824_18

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