In the current study, we examined the expressions of the BH3-only proteins, Bim, Noxa and Puma, and found that there was a correlation between these expressions and the clinicopathological features. While we also found that low Bim expression was significantly more prevalent in the Sq histology versus non-Sq histologu, this study revealed no significant correlations between any of the clinical variables and the expression of Noxa or Puma. Although there has been one pilot study that used immunohistochemistry to examine the expression of the BH3-only proteins, Bad, Bid and Bim, in NSCLC samples [17
], the current study is the first to clarify the frequency of Bim, Noxa and Puma in a large series of NSCLCs.
In another study of NSCLCs that reported a similar pattern, the results showed that while a loss of Bim was observed in 2 out of 22 samples in the Sq histology and in 0 out of 19 in the Ad histology, the loss was not statistically significant [17
]. Although many promising treatments have been recently developed for adenocarcinoma of the lung, including EGFR-TKI (tyrosine kinase inhibitor) and pemetrexed [1
], there are few optimal treatments that can be used for Sq. However, our results suggest the possibility that the loss of Bim expression in Sq might be related to resistance to these anticancer drugs.
Bim has previously been shown to have a role in tumor suppression [12
]. This is supported by our current data that showed a significant association between the loss of Bim expression and a high Ki67 expression, which is a marker of tumor proliferation. In addition, high Bim expression was correlated with well differentiated tumors. Taken together, this suggests that Bim may have an impact on both cell proliferation activity and tumor feature in NSCLC.
Bim has also been shown to be required for initiation of the apoptosis induced by EGFR-TKI in NSCLC cell lines with EGFR-TKI-sensitive mutations [27
]. Furthermore, inhibition of Bim induction has also been observed in NSCLC with the EGFR-TKI resistance mutation, T790M, which suggests that Bim induction leads to the active response of the EGFR-TKI treatment [28
]. Recently, BH3-mimetics have been developed and shown to have cytotoxic effects on many solid tumors [30
]. The BH3-mimetic, ABT-737, along with its oral analogue, AB7-263, have especially been shown to promote apoptosis and suppress tumor growth in small-cell lung cancer [32
]. Although it has been observed that several NSCLC cell lines show relative resistance to ABT-737 monotherapy [33
], ABT-737 significantly enhanced EGFR-TKI-induced cell killing of NSCLC, and thus, this combined treatment might be a promising new therapy [29
]. Although we have not examined the correlation between Bim expression and responses to treatment, our current data suggest that Bim expression might be involved with tumor proliferation and feature, which supports the notion that Bim expression could be a useful therapeutic marker.
Noxa and Puma expression levels have been investigated in various cancers, including colon cancer and ameloblastic tumors, and were shown not to have any clinical significance [35
]. This is consistent with our current data. To the best of our knowledge, there has been little data reported concerning the relationship between these two BH3-only proteins and the various clinicopathological factors in NSCLC. Unlike Bim expression, these two proteins may have not been implicated in the pathogenesis of NSCLC, which suggests that further investigations of their roles are warranted.
Our findings also did not find any impact of the examined BH3-only proteins on survival outcomes. Likewise, there have been no other reports on any relationships between these proteins and patient prognosis in NSCLC. However, it has been verified that both Bim and Puma expression are independent prognostic factors in colon cancer [14
]. Conversely, Bim expression has not been previously linked with patient prognosis in either gastric cancer or malignant mesothelioma [15
]. Therefore, the origin and stage (early or advanced) of the tumor in addition to the subsequent therapies that have been used against the disease might account for the prognosis discrepancies that have been described. Moreover, these proteins are known to be regulated by many different complex upstream pathways, such as AKT/PI3K, MAPK, or p53 [8
]. Thus, the various levels of pathway regulation that could potentially exist might also be contributing factors for the differences noted in the prognosis between the different types of malignant diseases.