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Original Article Expression and Prognostic Significance of MCM-3 and MCM-7 in Salivary Adenoid Cystic Carcinoma

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Original Article Expression and Prognostic Significance of MCM-3 and MCM-7 in Salivary Adenoid Cystic Carcinoma Int J Clin Exp Pathol 2018;11(11):5359-5369 www.ijcep.com /ISSN:1936-2625/IJCEP0085911 Original Article Expression and prognostic significance of MCM-3 and MCM-7 in salivary adenoid cystic carcinoma Qing-Liang Wen1,2,3*, Sen-Miao Zhu5*, Lie-Hao Jiang2,3*, Fang-Yue Xiang6, Wen-Juan Yin4, Yang-Yang Qian1,2,3, Yu-Qing Huang3,7, Ke-Xin Yin7, Xin Zhu8, Ming-Hua Ge1,2,3 1The First Affiliated Hospital of Wenzhou Medical University, Ouhai District, Wenzhou, China; 2Department of Thyroid and Breast Surgery, Zhejiang Provincial People’s Hospital, Gongshu District, Hangzhou, China; Depart- ments of 3Head and Neck Surgery, 4Pathology, Zhejiang Cancer Hospital, Gongshu District, Hangzhou, China; 5The Second Affiliated Hospital of Wenzhou Medical University, Lucheng District, Wenzhou, China; 6Stomatology Col- lege, 7Second Clinical Medical College, Zhejiang Chinese Medical University, Binjiang District, Hangzhou, China; 8Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Gongshu District, Hangzhou, China. *Equal contributors. Received September 24, 2018; Accepted October 25, 2018; Epub November 1, 2018; Published November 15, 2018 Abstract: This study sought to investigate minichromosome maintenance protein 3 (MCM3) and minichromosome maintenance protein 7 (MCM7) expression in salivary adenoid cystic carcinoma (SACC) samples, and to evaluate the relationship between clinicopathological characteristics and prognosis. The expressions of MCM3 and MCM7 were evaluated using immunohistochemistry of tissue sections from SACC patients, and statistical analyses were performed to evaluate the associations between MCM expression and clinicopathological variables and to analyze the disease-free survival (DFS) and prognostic factors. The positive expression rates of MCM3 and MCM7 in SACC were 98.8% and 96.6%, respectively. MCM3 expression correlated with T-stage and nerve invasion. MCM7 expres- sion correlated with T-stage, adjacent tissue invasion, nerve invasion, and prognosis, and was negatively associated with DFS. However, there was no significant correlation between MCM3 expression and DFS. A kappa analysis dem- onstrated that MCM3 was closely associated with MCM7. MCM7 may be a favorable prognosis indicator in SACC. Keywords: Salivary adenoid cystic carcinoma, MCM3, MCM7, immunochemistry, prognosis Introduction appears to be the effectiveness of radical surgi- cal resection [4]. Patients who are insensitive Adenoid cystic carcinoma (ACC), while being an to radiotherapy and chemotherapy often have uncommon malignancy, is one of the most com- poor prognoses, developing local recurrence mon salivary gland cancers. ACC accounts for and distant metastases [5]. approximately 10-25% of all salivary gland malignancies [1]. Salivary adenoid cystic carci- In order to more effectively diagnose and treat noma (SACC) is characterized by aggressive this cancer, the molecular mechanism underly- growth, a high rate of recurrence, nerve and ing SACC malignant progression needs to be blood vessel invasion, and frequent lung metas- further explored. The discovery of novel bio- tasis, which lead to a poor outcome [2]. SACC markers associated with metastasis and pro- usually occurs in middle-aged and elderly peo- gression is urgently needed so that drugs for ple (50-60 years). There are currently no obvi- effective targeted molecular therapies against ous risk factors associated with the occurrence SACC may be developed. and development of SACC. In addition, it is unknown whether smoking affects the inci- Tumorigenesis results from abnormal cell prolif- dence of SACC [3]. Until now, treatment for eration caused by cell cycle dysregulation, SACC has involved radical surgical resection which is related to the initiation of DNA replica- with additional radiotherapy and chemothera- tion. Sustained DNA replication plays a crucial py. The most significant factor in prognosis role in the occurrence and development of can- MCM-3 and MCM-7’s role in cystic carcinoma cer [6]. Proliferative proteins related to the cell regulated by, Cyclin D1-dependent kinase cycle, such as the minichromosome mainte- (CDK4), to bind the tumor suppressor protein nance (MCM) nuclear proteins, proliferating cell RB [15]. nuclear antigen (PCNA), and Ki-67, are involved in carcinogenesis [7]. It has been found that Ki67, a commonly-used proliferative marker, is not expressed in cells Members of the MCM protein family have simi- entering G1 from the G0 phase but is only lar molecular structures and biological func- expressed in actively-dividing cells. In contrast tions and include six major isoforms (MCM2-7), to Ki67, MCM is significantly highly expressed which are involved in the initiation and exten- in the G1 and S phases of the cell cycle, so it sion of DNA replication, and which prevent re- can potentially be used to detect cells entering replication in the same cell cycle [8]. It has G1 from the G0 phase. PCNA, another widely been confirmed that the expression level of used marker, is involved not only in DNA repli- MCM proteins is related to the periodicity of the cation, but also in its repair, and may thus be cell cycle, and that they are significantly highly present in large quantities when cells are not expressed in the G1 and S phases. However, actively proliferating. In contrast, MCM proteins the expression level of MCM is gradually are related only to the replication of DNA [16]. decreased, and may even be undetectable, Thus, MCM proteins may have higher accuracy during the G0 phase, differentiation, and than the traditional markers Ki67 and PCNA in senescence [9]. In the G1 phase, the replica- assessing cellular proliferative activity. In addi- tion licensing factor (RLF), which possesses tion, several studies have revealed that elevat- helicase activity and is composed mainly of ed expression of MCM is associated with poor stable heterohexamers formed by MCM2-7 pro- prognosis and malignant processes [17-19]. teins, combines with other related replication However, few studies have investigated the initiation factors to form a pre-replicative com- expression and prognostic utility of MCM in plex (pre-RC) that participates in DNA replica- SACC. In the present study, we aimed to investi- tion. The MCM proteins dissociate from the pre- gate the expression of MCM3 and MCM7 in RC and are in a free state during the S phase, SACC samples and evaluated the relationship and do not participate in the assembly of pre- between clinicopathological characteristics RC during replication. This prevents DNA repli- and prognosis. cation from re-initiating, ensuring that the DNA replicates only once per cell cycle [10]. Materials and methods It has been found that, in order to perform their Patients and samples biological function, MCM proteins assembled in the cytoplasm form heterohexamers before A total of 89 patients diagnosed with primary entering the nucleus. This is because mono- SACC by postoperative histopathological exam- meric MCM protein can be easily excreted from ination in Zhejiang Cancer Hospital from June the nucleus. Nuclear localization sequences 2002 to May 2013 were enrolled in this study. present in MCM2 and MCM3 proteins suggest All 89 clinical tumor samples, acquired from that they are responsible for providing chromo- the patients who had not undergone preopera- some-binding targets for other MCM proteins. tive chemotherapy or radiotherapy, were recon- The removal of MCM proteins from the nucleus firmed by three expert SACC pathologists, and is regulated by cyclin-dependent kinases. their clinical information was retrospectively However, it remains to be determined whether investigated. Tumor-node-metastasis (TNM) cyclin-dependent kinases promote the degra- staging, carried out according to the recom- dation of MCM polymers [11-13]. Moreover, mendation of the International Union Against each particular subunit has its own specific Cancer, was used to assess the extent of SACC function. For instance, MCM3 proteins have [20]. All the patients provided informed con- been shown to interact directly with MCM5/ sent before surgical treatment, and the study CDC46, which interacts with MCM3AP before obtained approval from the Ethics Committee being acetylated by MCM3AP (a chromatin- of Zhejiang Cancer Hospital. associated acetyltransferase). The initiation of DNA replication and cell cycle progression is The prognoses of the 89 primary SACC patients inhibited by the acetylation of MCM3 proteins were evaluated by regular follow-ups, which [14]. MCM7 proteins interact with, and may be included oral ultrasound and enhanced compu- 5360 Int J Clin Exp Pathol 2018;11(11):5359-5369 MCM-3 and MCM-7’s role in cystic carcinoma Figure 1. Clinical significance of MCM3 and MCM7 in SACC. Oncomine data mining analysis of MCM3 and MCM7 mRNA levels in Frierson HF salivary-gland statistics between normal salivary gland versus SACC. MCM3 and MCM7 expression in SACC by IHC. tational tomography of the oral cavity, at three- Evaluation of immunohistochemical staining month intervals after surgical treatment. We calculate the survival of the time interval Immunohistochemical assessment of the between the diagnosis day and the latest fol- expression of the MCM3 and MCM7 was per- low-up (or relapse or death). The median dura- formed by scanning each slide under low mag- tion of the follow-ups was 48 months (range nification (×100) to identify regions containing 3-145 months). Disease-free survival (DFS) positive immunoreactivity. At high magnifica- data were available for all the 89 (100%)
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