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IntroductionLung cancer is the foremost cause of cancer-related mortality, with high incidence rates, robust metastatic propensity, and frequent de novo and acquired resistance to therapy (1). Even in the setting of "addiction" to mutant receptor tyrosine kinases (RTKs) that are pharmacologically targetable, tumors undergo only transient responses to targeted therapy and subsequently develop drug resistance that frequently results in death (2). The incidence of KRAS mutations exceeds that of RTK mutations in lung adenocarcinoma, and currently available therapeutic strategies do not effectively target mutant KRAS (3). KRAS-mutant lung adenocarcinomas commonly harbor oncogenic mutations in TP53 and STK11 that confer metastatic capacity (4). Thus, inhibition of mutant oncoproteins reduces tumor burden but does not eradicate disease in patients with lung cancer, warranting the development of other treatment strategies that complement the beneficial effects of tumor cytoreduction.In the "migrating stem cell hypothesis," metastases arise from a small population of tumor cells with the capacity to undergo epithelial-mesenchymal transition (EMT), a reversible process characterized by a loss of polarized features, detachment from neighboring cells, increased motility and invasion, and resistance to standard cytotoxic chemotherapy (5). EMT is induced by several

Gliomas are the most common and deadly type of primary brain tumor. In this study, we showed that cAMP response element-binding protein (CREB), a proto-oncogenic transcription factor that is overexpressed in gliomas, can promote gliomagenesis by modulating the expression of oncogenic microRNA-23a (mir-23a). First, we found that CREB is highly expressed in glioma tissues and cell lines. CREB is also essential for glioma cell growth and cell survival in vitro and is critical for gliomagenesis in vivo. Second, microRNA microarray, ChIP-chip, ChIP-quantitative PCR, and luciferase reporter assays showed that CREB directly binds to the regulatory sequences of mir-23a and enhance the expression of mir-23a. Moreover, mir-23a was confirmed as a functional downstream target of CREB in glioma cell growth and cell survival. Finally, using computational prediction followed by experimental confirmation, we identified PTEN, which is frequently silenced in gliomas, as a downstream target of mir-23a. Taken together, we propose that CREB promotes gliomagenesis and acts as a modulator of oncogenic mir-23a, which represses the tumor suppressor PTEN.

Migration-proliferation dichotomy is a common mechanism in gliomagenesis; however, an understanding of the exact molecular mechanism of this “go or grow” phenomenon remains largely incomplete. In the present study, we first found that microRNA-9 (miR-9) is highly expressed in glioma cells. MiR-9 inhibited the proliferation and promoted the migration of glioma cells by directly targeting cyclic AMP response element-binding protein (CREB) and neurofibromin 1 (NF1), respectively. Our data also suggested a migration-inhibitory role for CREB through directly regulating the transcription of NF1. Furthermore, we found that the transcription of miR-9-1 is under CREB's control, forming a negative feedback minicircuitry. Taken together, miR-9 inhibits proliferation but promotes migration, whereas CREB plays a pro-proliferative and anti-migratory role, suggesting that the CREB-miR-9 negative feedback minicircuitry plays a critical role in the determination of “go or grow” in glioma cells.