Our study reports that TRA16 is highly expressed in NSCLCs and its expression level is negatively correlated with the overall survival of NSCLC patients, and it enhances ERβ signaling pathway by direct stimulation of ERβ activity and through suppressing TR2-inhibitory effect on ERβ for cancer cell growth, suggesting TRA16 is a promising diagnostic and prognostic biomarker and potential target in NSCLC.
Tumor biomarkers, such as CEA, CA125, NSE, CYFRA21-1, and p53, are currently used in cancer diagnosis and prognosis, but few of them are ideal for NSCLC because of low sensitivity and specificity (23
). For stage I NSCLC patients, the five-year survival rate exceeds 60%, but the patients with metastatic spread to regional or distant sites, who account for at least three quarters of lung cancer patients at the time of diagnosis, have only approximately 15% five-year survival rate (26
). Therefore, if the NSCLC can be diagnosed in early stages, the patient survival rate and time could be significantly improved. This study demonstrates that TRA16 is highly expressed in approximately 90% of NSCLCs, in which over 71% of stage I NSCLC overexpress TRA16, which is not expressed in lung benign diseases and normal lung tissues, indicating its potential for NSCLC diagnosis, especially for early stage NSCLC.
Furthermore, our findings of the correlation of increased expression of TRA16 with increased malignancy of NSCLC demonstrate that TRA16 could be a valuable biomarker to monitor the progression of the tumor, and provide physicians with useful information to evaluate the severity of the disease and to choose proper treatments for NSCLC patients.
For a long time, researchers have proposed that sexual hormone, such as progesterone and estrogen, may play important roles in lung cancer carcinogenesis and development (27
), which was supported by recent clinical findings of abnormal expression of ERβ (2
) and increased intratumoral estrodial concentration in NSCLC tissues (8
). There are several possible mechanisms that may be involved in the abnormal activation of hormone related signaling transduction pathways. First, the high serum hormone level or high hormone receptor expression level can up-regulate downstream signaling pathways to stimulate target cell proliferation (8
). Second, the mutation of hormone receptors may increase the ligand binding affinity or be activated by other ligands (29
). Third, the abnormality of hormone receptor co-factors can active the downstream signaling transduction pathway, and then promote oncogenesis (31
TRA16 belongs to the co-factors of nuclear receptors (NRs) with which it interacts to affect the transcriptional activity of NRs. Our findings that the concordant expressions of TRA16 and ERβ in NSCLC and their interaction suggest that TRA16 may serve as an upstream positive regulator of ERβ in NSCLC. Moreover, we have observed the interaction between TRA16 and TR2. Therefore, possible interactions among TRA16, TR2, TR4, and ERβ could be proposed. TR2 and TR4 inhibit ERβ signaling pathways. In addition to its direct stimulation of ERβ, TRA16 also directly interacts with TR2 and TR4 that results in the release of ERβ from TR2 and TR4 inhibition, which consequently leads to the tumorigenesis. Since it is highly and specifically expressed in tumor tissues, TRA16 may be used as a tumor-specific therapeutic target for lung cancer treatments in the form of anti-TRA16 antibody or TRA16 shRNA.
Therefore, there are still many questions to be answered, such as what are the upstream regulators of TRA16 and its interaction sites with ERβ and TR2, and whether the TRA16 expression can be detected in circulating cancer cells in patient blood that could be used to easily screen and diagnose patients with NSCLC, all of which will be investigated in future studies.