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ISSN : 1225-1577(Print)
ISSN : 2384-0900(Online)
The Korean Journal of Oral and Maxillofacial Pathology Vol.45 No.1 pp.1-10

Screening on ATG-Antigen Protein Related with Survival Rate on Clinicopathologic Factors in OSCC Patients

Mi Heon Ryu1), MinA Jang2), Uk-Kyu Kim3)*
1)Department of Oral Pathology, Education and Research Team for Life Science on Dentistry, and Dental and Life Science Institute, School of Dentistry, Dental and Life Science Institute, Pusan National University
2)Department of Oral Pathology, School of Dentistry, Pusan National University
3)Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University
* Correspondence: Uk-Kyu Kim, Department of Oral and Maxillofacial Surgery, School of Dentistry, Pusan National University, 49, Busandaehak-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea Tel: +82-55-360-5112, Fax: +82-55-360-5104 E-mail:
December 31, 2020 January 8, 2021 February 5, 2021


Autophagy is a cell survival mechanism that works for the survival of cells under various physiological and pathological conditions. ATG5 is a key protein in the process of autophagy propagation and is involved in tumor development and progression. Chemotherapeutic agents targeting ATG5 enhance the host's immune response in various human cancers and intensify the effectiveness of chemotherapy. However, the physiological role of ATG5 protein in oral squamous cell carcinoma (OSCC) has not been fully recognized. The purpose of this study was to examine the correlation between clinico-pathological factors of OSCC patients and ATG5 immunoexpression through immunohistochemistry (IHC) in the tissues of OSCC patients treated at our hospital, and to analyze the regarding influences and their mechanisms. The authors analyzed 20 OSCC patients from National University Dental Hospital, at Pusan National University from January 2002 to December 2007, which were eligible for the study. Data were obtained by reviewing the medical records of the OSCC patients, and ATG5 immunoexpression was obtained using IHC staining in the tissue samples of the OSCC patients. In the tissue sample of OSCC patients, the immunoexpression of ATG5 elevated, in comparison to the normal oral mucosa, and there was a significant correlation with Drinking, Pathological Stage. In regards to Cox regression analysis, Clinical stage, Tumor size, Histopathologic grade, Cervical nodal metastasis, Loco-regional recurrence, and ATG5 expression have statistically significant correlations. These results imply that the changes in the expression of ATG5 proteins in OSCC can be a prominent factor in the OSCC progression and the prognosis of OSCC patients.

구강암 환자의 생존율과 관련된 임상 영향인자들과 암 호발 항원단백인자 조사

유 미현1), 장 민아2), 김 욱규3)*
1)부산대학교 치의학전문대학원 구강병리학 교실, 부산대학교 치의생명과학 교육연구팀, 치의생명과학연구소
2)부산대학교 치의학전문대학원 구강병리학 교실, 치의생명과학연구소
3)부산대학교 치의학전문대학원 구강악안면외과학 교실


    Pusan National University(PNU)


    Oral squamous cell carcinoma (OSCC) is the most frequent malignant tumor in oral cavity. The frequency of OSCC is the 7th most frequent worldwide and it accounts for 3% of all cancer diagnoses1). The Ministry of Health and Welfare reported that it was the 10th most abundant disease for South Korean males (2.1%; including oropharynx)2). OSCC occurs mainly after the 40s, more often in the 60s. Moreover, it is 2-6 times more common in males. In addition, the habit of smoking and drinking are closely related to its occurrence frequency as well3). OSCC is high malignant disease, and the prognosis of OSCC tends to be poor because it is often diagnosed after carcinoma has already grown considerably4). Therefore, it is essential to understand the underlying mechanism of OSCC development to hold back the progression of OSCC and improve treatment strategy.

    Autophagy can appear under various conditions including nutrient restriction, and it is a catabolic process that decomposes cell ingredients, such as basal repair or stress response mechanism occurring within cells5). Autophagy is important for maintaining cellular nutrients and energy homeostasis and is essential for normal development. Defects in autophagy are closely related to a number of human diseases, including cancer.

    A series of protein complexes, which are composed of autophagy-related genes (ATGs) regulates the formation of the autophagosome. Macroautophagy progresses in the process of induction, nucleation, elongation, closure, maturation, fusion, and degradation6). The formation process of autophagosome is regulated by many protein types, including ATG5, Previous studies have shown that the higher ATG5 expression increases the sensitivity to apoptosis stimuli regardless of cell type as well as promotes autophagy.

    In yeast, the ubiquitin-like protein ATG12 creates a covalently bound to ATG5 by ATG7 and ATG10. ATG7 and ATG10 act as E1 activation and E2 conjugation enzymes, respectively. Thereafter, ATG16L1 forms a noncovalent bond to ATG5 and dimerizes to promote the expansion of the autophagosome membrane. In mammals, the ATG12-ATG5-ATG16L1 complex binds to the phagophore membrane, but it is dissociated after completing autophagosome. Golgi protein RAB33A can inhibit ATG16L1 by attaching to it, and ATG5, ATG7, and ATG12 are inhibited by KAT2B/p300 induced acetylation7).

    In the tumor microenvironment, autophagy plays an important role in carcinogenesis in response to metabolic stress. It can inhibit the survival of cancer cells in the early stage of tumor development8,9), and it is involved in cell adaptation and recurrence after cancer treatment in the late stage of tumor development10,11). However, progressive autophagy can also induce cell death, and progressive autophagy can express loss-of-function mutation in autophagy promoting genes in human carcinomas. Thus, autophagy is a double-edged sword in tumor development, and it can function as a tumor suppressor as well as a protector of cancer cell survival. Consequently, it is a complex and difficult task to explain the exact role of it in different stages of cancer progression and in treatment responses.

    OSCC takes place through a multistep carcinogenesis that develops to squamous carcinoma through the processes of precancerous lesion and carcinoma in situ. It is known that the oral multistep carcinogenesis is associated with the accumulation of complex genetic and acquired mutations, such as the inactivation of tumor suppressor genes, gene deletion, gene mutation, and activation of oncogenes due to the methylation of promotor during this process. Previous studies on autophagy in OSCC cell lines showed that ATG5 protein induced apoptosis or autophagy to OSCC cells. However, the roles of ATG5 protein in the prognosis of OSCC patients have not been studied.

    Therefore, this study targeted to analyze the effects of ATG5 protein in OSCC patients by examining the immunohistochemical expression of ATG5 in normal oral mucosal tissues and tissue samples of OSCC patients and analyze the relationship between ATG5 immunoexpression and clinico-pathological factors of OSCC patients.


    1. Tissue samples of OSCC patients

    This study used 20 OSCC tissue specimens, with good condition of paraffin block among biopsy samples collected at the Department of Oral and Maxillofacial Surgery at Pusan National University Dental Hospital from January 2002 to December 2007.

    Eleven normal oral mucosa (NOM) out of the tissues obtained during extraction of third molar, from the Department of Oral and Maxillofacial Surgery at Pusan National University Dental Hospital, were used. All tissue samples used in the study were utilized after obtaining approval from the Institutional Review Board (IRB) of Pusan National University Dental Hospital (PNUDH-2017-004).

    2. Histological review of tissue samples

    The biopsied NOM tissue and the tissue of OSCC patients were fixed using 10% neutral formalin solution for 24 hrs and washed with distilled water for 20 mins. Afterward, the samples were dehydrated using ethyl alcohol according to a conventional method, treated with xylene, and then embedded with paraffin. The embedded paraffin tissue was prepared into 4 μm-thick sections, followed by deparaffinization, ethyl alcohol hydration, and water washing. Subsequently, it was stained with hematoxylin and eosin (H/E stain), and then it was examined by an oral pathology specialist.

    3. The analysis of clinico-pathological factors of OSCC patients

    The authors recorded the gender, age at the time of diagnosis, drinking status, smoking habit, primary sites of OSCC, tumor size of OSCC, clinical stage, the histopathologic grade of OSCC, pathological stage, cervical nodal metastasis, loco-regional recurrence, survival months, and distance metastasis by examining the medical records of OSCC patients. The histopathologic grade of OSCC was classified into three categories (well differentiated, moderately differentiated, and poorly differentiated) and clinical stage of OSCC patients was classified according to the TNM Staging Classification criteria of the American Joint Committee on Cancer (2016, the 8th edition).

    4. Reagents and antibodies

    Primary antibodies against ATG5 were obtained from Abcam (Cambridge, UK), and secondary antibody (Poly HRP conjugate) was purchased from Invitrogen (Camarillo, CA, USA). In addition, 3, 3'-diamonobenzidine tetrahydrochloride (DAB) was acquired from Vector (CA, USA) and Mayer's hematoxylin was obtianed from Sigma Aldrich (St. Louis, USA).

    5. ATG5 Immunohistochemical staining of tissue samples

    Immunohistochemical staining was conducted after cutting a 4 μm-thick tissue section from paraffin-embedded block, prepared after a biopsy and mounting it into slide glass. The slide was treated with xylene three times for 7 mins each at room temperature (RT) to remove paraffin. Afterward, the rehydration process of the slides was carried out by immersing the sections in 100%, 90%, 80%, and 70% ethyl alcohol, sequentially. Then, the slide was clearly washed with phosphate buffered saline (PBS) 3 times for 5 mins each, and it was immersed in 3% hydrogen peroxide solution and reacted with it for 20 mins at RT to inhibit endogenous peroxidase in the tissue to be stained. Thereafter, it was reacted with goat serum at RT for 30 mins to inhibit the binding of non-specific protein. After diluting ATG5 antibody at 1:100 as a primary antibody, it was reacted with it overnight at 4°C. After letting it react with a secondary antibody for 30 mins at RT, and chromogen was developed with DAB. It was then sealed after performing contrast counerstaining using Mayer's hematoxylin. Breast cancer tissue was used as the positive control of ATG5 IHC staining, and the negative control was prepared by using PBS instead of the primary antibody and processing the sample with the same staining process. They were compared afterward using light microscope.

    Five different locations on each slide were randomly selected with an light microscope, and each location was photographed using a light microscope equipped with a digital camera (Olympus, BH-2, Tokyo, Japan). The level of immunoreactivity was determined based on the percentage of cells stained with ATG5 protein compared to the total number of cells: when it was stained less than 5%, it was classified as 0 point; when it was stained equal to or more than 5% and less than 10%, it was classified as 1 point; when it was stained equal to or more than 10% and less than 50%, it was classified as 2 points; when it was stained equal to or more than 50% and less than 75%, it was classified as 3 points; and when it was stained equal to or more than 75%, it was classified as 4 points. Stain intensity was classified as follows: negative (score 0), weak (score 1), moderate (score 2), and strong (score 3). Each score was calculated by multiplying the level of immunoreactivity and stain intensity. The representative value of each case was established by averaging the five calculated scores of each slide12).

    6. Statistical analysis

    The χ2 test was performed to assess the difference in the immunoreactivity of ATG5 protein in NOM and OSCC tissues. Moreover, the correlation between the clinico-pathological factors of the OSCC patients (gender, age at the time of diagnosis, drinking, smoking, primary sites, tumor size, clinical stage, the histopathologic grade of OSCC, pathological stage, cervical nodal metastasis, loco-regional recurrence, survival months, and distance metastasis) and the immunohistochemical staining results of ATG5 protein were analyzed using Spearman correlation analysis. The survival months of OSCC patients were analyzed using Cox regression model and Kaplan-Meier survival analysis.

    Statistical analyses were performed using the SPSS 25.0 (SPSS Inc., NY, USA) program. Statistical significance was determined as p<0.05.


    1. Characteristics of the OSCC patients

    The age of OSCC patients ranged from 30 to 78 years, and most OSCC patients were in their 50s and 60s. The gender ratio of the OSCC study subjects was 2.3:1 (male:female). OSCC occurred most commonly at the mandible and maxilla followed by tongue and other regions (Table 1).

    The most common histopathologic grade of OSCC was Well differentiation, and the average of survival month was 81.1±78.3. The most common clinical stage was the advanced stage (stage III and IV) with 6 cases of loco-regional recurrence, 7 cases of smoking, and 8 cases of drinking.

    2. The difference in the expression of ATG5 protein

    The results of IHC staining revealed that ATG5 protein showed a weak positive reaction in the cytoplasm of NOM’s epithelial cells and a strong positive reaction in both cytoplasm and nucleus in OSCC. The expression of ATG5 protein was significantly higher in OSCC than in NOM (p<0.05, Fig. 1).

    3. Correlation with the clinico-pathological factors of OSCC patients

    The protein expression of ATG5 was significantly correlated with drinking and pathological stage, while gender was significantly correlated with drinking, smoking, clinical stage, and tumor size. Moreover, drinking had a significant correlation with ATG5 expression, gender, smoking, and clinical stage, and tumor size had a significant correlation with gender and pathological stage. Pathological stage was correlated with ATG5 expression, tumor size, cervical nodal metastasis, and survival months. Cervical nodal metastasis was correlated with pathological stage and survival months (Table 2).

    4. Cox regression and Kaplan-Meier survival graph analysis

    A multivariate Cox regression test was performed to identify variables affecting survival rate. The analysis results showed that clinical stage, tumor size, histopathologic grade, cervical nodal metastasis, locoregional recurrence, and ATG5 expression were significant variables (Table 3).


    OSCC is the most common cancer in the oral cavity, and accounts for 90-95% of all oral cancers. It is known that many types of gene mutations are involved in the multi-step carcinogenesis of oral cancer, and, among them, a lot of variations in the expression of autophagy-related genes have been reported. Ubiquitin-like ATG12 conjugates with ATG5 in the process of forming autophagosome, which is important for autophagy, ATG12-ATG5 conjugate acts as an E3ligase to promote the conjugation of ATG5 and phosphatidylethanolamine (PE)13).

    Most studies on autophagy in OSCC examined the mechanism of the genotoxic effect when treating OSCC cell lines with drugs. Ahn et al. reported that apoptosis and autophagy occurred at the same time when YD10B cell, the OSCC cell line, was treated with 2'-hydroxycinnamaldehyde (HCA) and HCA-induced autophagy controlled apoptosis14).

    ATG proteins are considered to be involved in the development and progression of tumors15). Cho et al. reported that the ATG5 expression in colorectal cancer was lower than the ATG5 in the normal colon mucosa around the tumor and ATG5 expression was associated with lymphovascular invasion16). However, it was reported that the immunoexpression of ATG5 increased in prostate cancer17) and the degree and role of ATG expression varied by the type and tissue of the tumor.

    An increase of cytoplasmic p62 was presented by recent studies that reported the association between autophagy and cancer progression and a study conducted immunohistochemical staining in OSCC. It was significantly related with aggressive clinicopathologic features and unfavorable prognosis. It was also reported that functional autophagy is involved in the tumor progression of OSCC in the early stage18). It is believed that LC3 and p62, hall markers of autophagy, are associated with the infiltration of T cells and autophagy influences the mobilization of immune cells. Moreover, it was reported that autophagy-related proteins are associated with malignant potential and unfavorable prognosis19). The results of these studies implied that autophagy impairment contributes to the progression of oral cancer substantially.

    Smoking habit and drinking are important etiologies of OSCC. They can independently affect the occurrence of OSCC, and they can generate synergism to increase the occurrence of OSCC. As the frequency of exposure to smoking and alcohol increases, the risk of OSCC tends to increase. Drinking can promote or activate the genotoxicity of carcinogens, interfere with DNA repair, and inhibit the detoxification of carcinogens. Therefore, it can generate synergy with smoking20-23). However, the effects of smoking and drinking on ATG5 expression were not significant in this study and they did not significantly influence the survival rate of OSCC patients. Although some studies argued that the OSCC, occurred in the oropharynx and tongue of young patients, especially young Caucasian males, often did not have the risk of alcohol and/or tobacco exposure, contrary to the common OSCC patients24). Our study had a limitation of small sample size, and further studies are needed to be conducted using more cohorts.

    The results of this study showed that ATG5 expression was significantly related to drinking and pathological stage, which indicated that ATG5 expression increased as the carcinoma condition was aggravated. Moreover, the pathologic stage showed an inverse correlation with the survival months (Spearman correlation coefficient = -.454; p = 0.044). The results of the Kaplan Meier survival analysis did not demonstrate a significant relationship between ATG5 expression and patients’ survival (data not shown). The analysis results of this study inferred that a higher ATG5 expression would decrease the survival rate.

    The results of Cox regression analysis revealed that, among the factors significantly affecting survival rate, clinical stage, tumor size, histopathologic grade, cervical nodal metastasis, locoregional recurrence, and ATG5 expression had a high level of relative risk. They were factors that have an important influence on prognosis and survival rate. Even with OSCC in a low clinical stage, the probability of occult metastasis is high. Therefore, it is possible to increase patient survival outcome by carrying out prophylactic neck dissection25). In addition, if local recurrence occurs in the primary surgical site, the prognosis will worsen and the survival rate of OSCC patients will decrease consequently because complete surgical excision is often difficult.

    Autophagy is well known as a molecular target of chemotherapy for treating various carcinoma types, and it is known to be related to cancer drug resistance26,27). In the case of malignant melanoma, autophagy has been reported as a prognostic factor and therapeutic target28). Zhu et al. conducted 3D culture using the Chronic myeloid leukemiaa cell line and reported that inhibition of autophagy induced by interferon type 1 promoted the apoptosis related to the caspase 8-BID pathway29). The results suggested the possibility of autophagy’s immunotherapy. Pei et al. reported that the MTDH gene induced the autophagy of gastric cancer cells due to the acceleration of the AMPK/ATG5 pathway and resulted in drug resistance30). This finding suggested that a pathway involving ATG5 in autophagy induction could regulate drug resistance. These results implied that ATG5 expression had a possibility as a chemotherapeutic target, especially in the OSCC cases with increase of ATG5 expression.

    Identifying the oncogene and understanding the function in the cancer development are critical in predicting the prognosis of the cancer and determining the treatment strategy. The results of this study indicated that increased ATG5 played a key role in the development and progression of OSCC and was associated with the prognosis of OSCC patients. Moreover, it is believed that increased ATG5 expression can be a novel biomarker that can be usefully used in the prognosis of OSCC. The results of this study can provide the basis for implementing chemotherapy for OSCC patients based on autophagy mechanisms.


    The analysis results of the ATG5 protein expression in the normal oral mucosa and OSCC showed that the expression of ATG5 protein increased in OSCC. ATG5 expression was significantly correlated with drinking and pathological stage, and gender was significantly correlated with drinking, smoking, clinical stage, and tumor size.

    In addition, the Cox regression analysis implied that clinical stage, tumor size, histopathologic grade, cervical nodal metastasis, locoregional recurrence, and ATG5 expression were correlated. These results suggested that the change in the expression of ATG5 protein was an important factor in the progression of OSCC and the prognosis of OSCC patients. Therefore, it will be necessary to elucidate the mechanism of OSCC progression and the increase of ATG5 protein expression in OSCC.


    This work was supported by a 2-Year Research Grant of Pusan National University



    Immunohistochemical stain of ATG5 protein in NOM (A) and OSCC tissue (B). ATG5 protein showed a weak positive reaction in the epithelial cytoplasm of NOM whereas a strong positive reaction in both cytoplasm and nucleus in OSCC tissues (scale bar, 1000 μm). ATG5 Immunreactvity was quantified. (p–0.000, Chi-square test).


    The χ2 Analysis between Clinico-pathological Factors of OSCC Patients and ATG5 immunoreactive Value

    Spearman correlation coefficient for OSCC Patients

    Cox Proportional Hazards Model Survival Analysis for OSCC Patients


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