TGF-β has paradoxical effects on cancer cell proliferation, as it suppresses proliferation of normal epithelial and low-invasive cancer cells, but enhances that of high-invasive cancer cells. However, how cancer cells acquire the ability to evade the tumor-suppressing effects of TGF-β, yet still take advantage of its tumor-promoting effects, remains elusive. Here, we identified miR-106b as a molecular switch to determine TGF-β effects on cell proliferation. TGF-β1 enhances the transcription of miR-106b via a promoter independent of its host gene MCM7 by activating c-jun. In high-invasive breast cancer cells, miR-106b is upregulated by TGF-β1 at a much higher level than that in normal or low-invasive cancer cells. Accumulation of miR-106b counterbalances TGF-β growth-inhibiting effects by eliminating activated retinoblastoma (RB) and results in enhanced proliferation. Furthermore, miR-106b mediates TGF-β effects on tumor growth and metastasis in breast cancer xenografts. In addition, miR-106b expression is elevated in higher stage tumors and correlated with tumor progression in breast cancer patients. These findings suggest that high level of miR-106b induced by TGF-β determines the tumor-promoting effects of TGF-β in breast cancer.

Despite abundant data supporting c-Src as a metastasis-promoting oncogene, activating mutations of c-Src are rare. This suggests that trans-interacting proteins may have a critical role in regulating c-Src activation. Here, we first report the discovery of Src homology 3 (SH3) domain-binding glutamic acid-rich-like protein (SH3BGRL), a novel c-Src activator in mice. Ectopic expression of murine SH3BGRL (mSH3BGRL) strongly promoted both tumor cell invasion and lung metastasis. Molecularly, mSH3BGRL specifically bound the inactive form of c-Src phosphorylated at Tyr527, promoting Tyr416 phosphorylation of c-Src and subsequent FAK-mediated activation of ERK and AKT signaling pathways. Targeting endogenous c-Src alone was sufficient to abolish mSH3BGRL-induced cancer metastasis in vivo. Unexpectedly, human SH3BGRL (hSH3BGRL) in turn suppressed tumorigenesis and metastasis in nature. We attempted site-specific reversion of hSH3BGRL amino-acid sequence to mSH3BGRL and found V108A substitution sufficient to restore SH3BGRL function as a c-Src activator and metastasis promoter. Notably, the somatic mutation R76C of hSH3BGRL can similarly act as hSH3BGRL-V108A and mSH3BGRL in tumorigenesis and metastasis. Our results uncover an evolutionarily controversial role of SH3BGRL in driving tumor metastasis through c-Src activation, and suggests that hSH3BGRL mutation status could be relevant to cancer diagnosis and therapy.

PurposeTo study the characteristic morphology and quantitatively evaluate the eye shape in different types of myopic maculopathy.MethodsA total of 103 eyes from 65 patients with high myopic maculopathy were examined by spectral-domain optical coherence tomography (SD-OCT) and three-dimensional magnetic resonance imaging (3D MRI). The participants were classified into two groups, namely myopic traction maculopathy (MTM) eyes and non-MTM eyes, with SD-OCT imaging. Volume renderings and morphology analysis of the 3D MRI of the eyeball were obtained. Quantitative analysis was achieved in the calculation of vitreous volume and the three-dimensional diameters of the eyeball in three cardinal axes. The eye shape distribution and the diameters of the eyeball were compared between the two groups. Eye shape distribution, vitreous volume, and eyeball diameter were compared between MTM and non-MTM eyes.ResultsThe MTM and non-MTM groups had a total of 68 and 35 eyes, respectively. A significant difference was found in the eye shape distribution (P<0.0001) between MTM and non-MTM eyes. Most of the MTM eyes had undergone a non-uniform expansion of the eyeball, whereas the non-MTM eyes had expanded uniformly. There was no significant difference (P>0.05) in either vitreous volume or other diameters between the two groups.ConclusionsNon-uniform globe expansion and staphyloma formation might play an important role in the pathogenesis of MTM.

No abstract