Lung adenocarcinoma, a major subtype of non-small-cell lung carcinomas (NSCLC), is one of the most deadly human carcinomas, accounting for approximately one third of all lung cancer cases. Distinguished from lung squamous cell carcinoma, lung adenocarcinoma has its unique biological and clinical characteristics, such as frequent mutations of epidermal growth factor receptor and anaplastic lymphoma kinase. Despite advances in diagnosis and compositive therapy, the overall survival rate for patients with lung adenocarcinoma is still low. The main reason of cancer-related mortality is lymph node metastasis. Therefore, prediction of regional lymph node status and patient survival is important, because it can influence the choice of treatment strategies.
Tiam1 was originally identified a metastasis-related gene of T lymphoma. As one of the guanine nucleotide exchange factors (GEFs), it was crucially involved in a variety of tumor signaling pathway through the regulation of Rho GTPases functions. HOU et al. found that down-regulation of Tiam1 using RNA interference resulted in inhibition of in vitro invasiveness in giant-cell lung carcinoma cells . Liu et al. reported that Tiam1 gene plays an important role in the proliferation, invasion, and metastasis of colorectal cancer cells . Tiam1 expression was suggested to be closely associated with motility in human breast cancer cell lines and was necessary to maintain the motile phenotype . Studies also showed that up-regulation of Tiam1 was associated with metastasis of hepatocellular carcinoma  and gastric cancer . These data indicated that Tiam1 expression can induce invasion and metastasis of tumor cells. And more notably, high expression of Tiam1 in tumor cells, implying a poor prognosis, has been observed in several solid tumors. For example, high Tiam1 expression is an independent predictor of decreased disease-free survival for patients with prostate cancer . Overexpression of Tiam1 correlates with poor prognosis in hepatocellular carcinoma . Recently, Du et al. has suggested that high Tiam1 expression is associated with poor overall survival in patients with primary gallbladder carcinoma . Nevertheless, whether these finding of Tiam1 can be extended to lung adenocarcinoma remains elusive.
In this study, we analyzed the expression of Tiam1 in 98 cases of lung adenocarcinoma tissues using immunohistochemistry. We found that Tiam1 expression was upregulated in lung adenocarcinoma compared to normal lung tissues, which suggest that Tiam1 like other members of the GEFs family, has an oncogenic role in the tumorigenesis of lung adenocarcinoma. Our finding is in consistence with previous studies that Tiam1 expression was found in multiple different cancer tissues, confirms a significant relation between Tiam1 expression and genesis and development of lung adenocarcinoma.
Our analysis further showed that Tiam1 overexpression correlates with lymph node metastasis of patients with lung adenocarcinoma, which suggests that Tiam1 might play an important role in the progression and invasion of lung adenocarcinoma. This result strongly supports our previous observation that Tiam1 expression was closely associated with 1ymph node metastasis in NSCLC . In addition, evidence also suggested that expression of Tiam1 is closely associated with lymph node metastasis in other tumor tissues [25, 26]. Molecularly, Tiam1 participates in cytoskeleton reorganization, cell adhesion and cell migration. Thus, we anticipate that Tiam1 may reshape lung cancer cells to make them easier to spread to the lymph nodes or enhance reciprocity between tumor and stroma, though the precise molecular mechanism of Tiam1’s action in lung adenocarcinoma remains to be clarified. These results indicate that Tiam1 expression in lung adenocarcinoma may be predictive of lymph node metastasis. With this approach, patients at high risk of lymph node metastasis could be identified for more aggressive treatment.
In the current study, we are the first to report the prognostic value of Tiam1 expression for patients with lung adenocarcinoma. According to Kaplan–Meier survival analysis, Tiam1 protein expression was found to be inversely correlated with patient’s overall survival. Increased expression of Tiam1 protein was significant predictor of poor prognosis for patients with lung adenocarcinoma, especially for patients with stage I-II cancer. Multivariate analysis revealed a significant negative relationship between the Tiam1 overexpression and overall survival. Therefore, we can conclude that Tiam1 serves as a biomarker for predicting prognosis of lung adenocarcinoma patients. Since Tiam1 overexpression can be a new predictor of poor prognosis of patients in a variety of tumors, it may be served as a new and independent predictor of prognosis for patients with lung adenocarcinoma as well. Yet, due to our limited sample size, with only six patients of stage IV, the observed association of Tiam1 expression with pathological stage should be verified by further studies.
In summary, expression of Tiam1 protein was significantly higher in lung adenocarcinoma tissue than in normal tissue. Higher Tiam1 expression is associated with lymph node metastasis, and is also an independent prognostic marker of poor survival in patients with lung adenocarcinoma. Tiam1 may serve as a useful molecular marker for lung adenocarcinoma progression and invasion. However, further studies are needed to verify our current findings, and we will investigate whether Tiam1 is a useful therapeutic target in lung adenocarcinoma.