論文の公開元へFunctional analysis of mitochondria-mediated ovarian carcinoma immune-reactive antigen domain 2 in lung adenocarcinoma
概要
1.1 Importance of treatment for lung cancer
Lung cancer is one of the most common cancer and leading causes of cancer related death worldwide (1, 2). One of the reasons lung cancer has the highest mortality rate is its late diagnosis at a very advanced stage. Although many molecular targeted drugs such as tyrosine kinase inhibitors for EGFR, ALK, and BRAF have been developed for advanced-stage lung adenocarcinoma, there are several limitations for complete cure. Therefore, it is urgent need to find new therapeutic approaches aiming for complete cure.
1.2 Histopathology of lung adenocarcinoma
Lung cancer can be divided into two categories, small-cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC). Adenocarcinoma is the most frequent subtype of non-small cell lung cancer (NSCLS) accounting for approximately 40% of lung cancer. In contrast to squamous cell carcinoma mainly caused by smoking, adenocarcinoma has been implied to relate with various genetic alterations (Fig. 1).
1.3 Noguchi classification for early-stage lung adenocarcinoma
Noguchi et al. have demonstrated that adenocarcinoma in situ (AIS, Noguchi classification type A and type B) has extremely favorable outcome, with a 5-year survival rate of 100%. AIS shows stepwise progress to early but invasive adenocarcinoma (eIA, Noguchi classification type C), which has a relatively poorer outcome, with a 5-year survival rate of 75%. According to the histological stepwise progression of adenocarcinoma, it is possible to investigate the molecular mechanism of lung adenocarcinoma progression at early stage to find novel biomarkers for early detection and therapeutic target for early-stage lung adenocarcinoma (Fig. 2).
In this regard, previously our group identified novel genes contributing early-stage of lung adenocarcinoma, including stratifin (SFN), ovarian cancer immunoreactive antigen domain containing 2 (OCIAD2), and epithelial cell transforming sequence 2 (ECT2), which show significantly higher expression in eIA compared with AIS (Fig.3).
Among them, I recently discovered a molecular mechanism that SFN inhibits the function of SCFFBW7, which specifically ubiquitinates oncoproteins such as cyclin E1, c-Jun, c-Myc, and Notch1, by binding to SKP1, a member of the SCF ubiquitin ligase complex, resulting in stabilization of these oncoproteins in lung adenocarcinoma (3).
This time, I drew attention to another molecular marker, OCIAD2.
1.4 The characteristic of ovarian cancer immunoreactive antigen domain containing 2 (OCIAD2) in lung adenocarcinoma
OCIAD2 was originally identified by Strausberg et al 2002 as a sequential similarity of ovarian carcinoma immune-reactive antigen domain 1 (OCIAD1) which was found in ascites fluid of patients with metastatic ovarian cancer and mapped to chromosome 4p11 through the National Institutes of Health Mammalian Gene Collection project (4). OCIAD2 is known to be localize at endosomes, mitochondria, and mitochondria- associated ER membrane (MAM) in several type of cells. (5, 6) On the other hands, there are limited information for subcellular localization of OCIAD2 in lung adenocarcinoma.
Up to date, our diagnostic pathology group has revealed that high OCIAD2 expression was found only in invasive adenocarcinoma of the lung and could be a promising biomarker of it by cytological and histological diagnosis. Also, its high expression in lung adenocarcinoma was significantly associated with poorer patient’s survival (7-9). Thereby, OCIAD2 would be a cancer-specific protein and potential biomarker for detection of early invasive adenocarcinoma.
Despite several reports have placed emphasis on high OCIAD2 expression in malignant tumors such as ovaries and brains (10-12), there were also reports that OCIAD2 is less likely to express in patients with hepatoblastoma or chronic lymphocytic leukemia (13, 14). Therefore, the precise function of OCIAD2 is still debatable. Moreover, the role of OCIAD2 and its specific molecular mechanism of its in early invasive adenocarcinoma have never been reported.
1.5 OCIAD2 in mitochondria
Mitochondria are composed of two membranes: outer and inner membranes. The inner membrane is further divided into an inner boundary membrane (IBM) and a cristae membrane (CM). Cristae have a tube or sheet-like shape. The cristae’s characteristic wrinkle shape greatly increases the surface area of the inner membrane, and this high surface area is known to increase the ATP-generating capacity. In addition, it is a major site of the oxidative phosphate cycle, and contains a complex of the respiratory chain such as NADH dehydrogenase (complex I), succinate dehydrogenase (complex II), cytochrome bc1 complex (complex III), cytochrome c oxidase (complex IV), and ATP synthase (complex V) and F1Fo-ATP synthase (15, 16). However, recently, interest in classical mitochondria and their respiratory system, as well as their relationship to mitochondria and malignancies, has been increasing (17, 18).
Furthermore, mitochondria play a role in cellular energy, metabolism, regulation of apoptosis, and various signaling pathway (19, 20). Especially, mitochondria are essential for the cellular apoptosis process such as intrinsic or extrinsic signaling. Since OCIAD1 is reported to contribute to neuronal sensitivity in Alzheimer’s disease by facilitating mitochondrial associated apoptosis (21), I expected that OCIAD2 also has a specific function related to mitochondria-initiating apoptosis in lung adenocarcinoma. In the present study, I demonstrated the subcellular localization of OCIAD2 in lung adenocarcinoma tissues and cell lines.
Then I revealed the oncogenic function of OCIAD2 related to cancer cell proliferation, migration, invasion, and cellular apoptosis. I showed that OCIAD2 controls cytochrome c release, mitochondrial membrane potential, and morphological integrity of mitochondria, leading to obstruction of apoptosis. In conclusion, the current study establishes results for several previously reported findings of OCIAD2 and suggests novel tumor-specific roles and potential therapeutic strategies.
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