Accumulating data have shown the involvement of microRNAs in cancerous processes as either oncogenes or tumor suppressor genes. Here, we established miR-30a as a tumor suppressor gene in breast cancer development and metastasis. Ectopic expression of miR-30a in breast cancer cell lines resulted in the suppression of cell growth and metastasis in vitro. Consistently, the xenograft mouse model also unveiled the suppressive effects of miR-30a on tumor growth and distal pulmonary metastasis. With dual luciferase reporter assay, we revealed that miR-30a could bind to the 3'-untranslated region of metadherin (MTDH) gene, thus exerting inhibitory effect on MTDH. Furthermore, we demonstrated that silence of MTDH could recapitulate the effects of miR-30a overexpression, while overexpression of MTDH could partially abrogate miR-30a-mediated suppression. Of significance, expression level of miR-30a was found to be significantly lower in primary breast cancer tissues than in the paired normal tissues. Further evaluation verified that miR-30a was negatively correlated with the extent of lymph node and lung metastasis in patients with breast cancer. Taken together, our findings indicated miR-30a inhibits breast cancer proliferation and metastasis by directly targeting MTDH, and miR-30a can serve as a prognostic marker for breast cancer. Manipulation of miR-30a may provide a promising therapeutic strategy for breast cancer treatment.

Abnormal morphologic changes are observed in aqueous tear deficiency that are more severe in Sjögren syndrome. The distinct changes of corneal nerves include increased nerve number, tortuosity, and chances of branching, suggesting an attempted nerve regeneration. A strong correlation exists between the changes of nerve morphology and the degree of dry eye. These results provide some possible evidence for the abnormal corneal sensation in dry eye.

Tumor hypoxia was first described in the 1950s by radiation oncologists as a frequent cause of failure to radiotherapy in solid tumors. Today, it is evident that tumor hypoxia is a common feature of many cancers and the master regulator of hypoxia, hypoxia-inducible factor-1 (HIF-1), regulates multiple aspects of tumorigenesis, including angiogenesis, proliferation, metabolism, metastasis, differentiation, and response to radiation therapy. Although the tumor hypoxia response mechanism leads to a multitude of downstream effects, it is angiogenesis that is most crucial and also most susceptible to molecular manipulation. The delineation of molecular mechanisms of angiogenesis has revealed a critical role for HIF-1 in the regulation of angiogenic growth factors. In this article, we review what has been described about HIF-1: its structure, its regulation, and its implication for cancer therapy and we focus on its role in angiogenesis and cancer.

Salivary gland carcinomas are a heterogeneous group of tumors with many histological subtypes which occur in both major and minor salivary glands. However, they have a relatively low of incidence. Their rarity limits study size and the ability to perform phase III trials. Therefore, to date, the entire management is usually varied. Certain published studies have paid more attention to the systemic therapy in the management of metastatic or locally recurrent salivary gland cancer, while little effort has been made to study the entire management for this lesions. Although results of treatment for patients with salivary gland carcinoma have improved in recent years, the treatment of salivary gland cancers is still not standardized. And some patients who haven’t received optimal treatment strategies had a reduced survival. In this review, the topics covered include surgery and radiotherapy, selective neck dissection, chemotherapy, and targeted therapy, which aimed to summarize the optimal management approaches and to develop recommendations for managing this lesions. For these rare cancers, there is also a need for a determined, coordinated effort to conduct high-quality clinical trials.

The progression of localized breast cancer to distant metastasis results in a poor prognosis and a high mortality rate. In this study, the contributions of miRNAs to tumor progression and the regulatory mechanisms leading to their expression alterations were investigated. Using highly lung-metastatic sub-lines from parental breast cancer cells, miRNA expression profiling revealed that the miR-17-92 cluster is significantly downregulated and the miR-18a-5p is the most evidently decreased. Ectopic expression and inhibition of miR-18a-5p demonstrated its capacity in suppressing migration and invasion of breast cancer cells. Further research identified sterol regulatory element binding transcription protein 1 (SREBP1), the master transcription factor that controls lipid metabolism, as a candidate target of miR-18a-5p. SREBP1 is overexpressed and strongly associated with worse clinical outcomes in breast cancer. Functionally SREBP1 promotes growth and metastasis of breast cancer both in vitro and in vivo. To unravel the underlying mechanism of SREBP1-mediated metastasis, mRNA profiling and subsequent gene set enrichment analyses (GSEA) were performed and SREBP1 was demonstrated to be significantly associated with epithelial-mesenchymal transition (EMT). Furthermore, SREBP1-mediated repression of E-cadherin was found to be deacetylation dependent and was augmented by recruiting Snail/HDAC1/2 repressor complex. In the light of these data, we propose that reduced expression of miR-18a-5p and concomitant overexpression of SREBP1 lead to induction of EMT states that in turn, promote breast cancer progression and metastasis. Taken together, our study reveals the crucial role of miR-18a-5p and SREBP1 in the EMT and metastasis, thus providing promising drug targets for tailored therapy in the advanced breast cancer setting.

PurposeLimbal epithelial stem cells (LSCs), located in the basal layer of the corneal epithelium in the corneal limbus, are vital for maintaining the corneal epithelium. LSCs have a high capacity of self-renewal with increased potential for error-free proliferation and poor differentiation. To date, limited research has focused on unveiling the composition of the limbal stem cell niche, and, more important, on the role the specific stem cell niche may have in LSC differentiation and function. Our work investigates the composition of the extracellular matrix in the LSC niche and how it regulates LSC differentiation and function.MethodsHyaluronan (HA) is naturally synthesized by hyaluronan synthases (HASs), and vertebrates have the following three types: HAS1, HAS2, and HAS3. Wild-type and HAS and TSG-6 knockout mice—HAS1−/−;HAS3−/−, HAS2Δ/ΔCorEpi, TSG-6−/−—were used to determine the importance of the HA niche in LSC differentiation and specification.ResultsOur data demonstrate that the LSC niche is composed of a HA rich extracellular matrix. HAS1−/−;HAS3−/−, HAS2Δ/ΔCorEpi, and TSG-6−/− mice have delayed wound healing and increased inflammation after injury. Interestingly, upon insult the HAS knock-out mice up-regulate HA throughout the cornea through a compensatory mechanism, and in turn this alters LSC and epithelial cell specification.ConclusionsThe LSC niche is composed of a specialized HA matrix that differs from that present in the rest of the corneal epithelium, and the disruption of this specific HA matrix within the LSC niche leads to compromised corneal epithelial regeneration. Finally, our findings suggest that HA has a major role in maintaining the LSC phenotype.

ObjectiveThe present study aimed to explore the clinical significance of neutrophils infiltration and carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1) expression in the tongue squamous cell carcinoma (TSCC), and to probe the possible relationship between them.Materials and MethodsTissue microarray and immunohistochemistry were used to detect neutrophils density and CEACAM1 expression in 74 cases of primary TSCC specimens and 17 cases of corresponding peritumoral tissues. The relationship of CEACAM1 expression and neutrophils density with clinicopathologic parameters and cancer-related survival of TSCC patients were evaluated. The correlation between CEACAM1 expression and neutrophils density was also evaluated. Real-time quantitative transcription polymerase chain reaction (qRT-PCR) was used to explore the possible molecular mechanisms between CEACAM1 expression and neutrophils infiltration.ResultsImmunohistochemistry evaluation revealed that there was more neutrophils infiltration in TSCC tissues than in peritumoral tissues. High neutrophil density was associated with LN metastasis (P = 0.01), higher clinical stage (P = 0.037) and tumor recurrence (P = 0.024). CEACAM1 overexpression was also associated with lymph node metastasis (P = 0.000) and higher clinical stage (P = 0.001). Survival analysis revealed that both neutrophils infiltration and CEACAM1 overexpression were associated with poorer cancer-related survival of TSCC patients (P<0.05), and neutrophils infiltration was an independent prognostic factor for TSCC (P<0.05). Furthermore, overexpression of CEACAM1 was correlated with more neutrophils infiltration in TSCC tissues (P<0.01). qRT-PCR results showed that CEACAM1-4L can upregulate the mRNA expression of IL-8 and CXCL-6, which were strong chemotactic factors of neutrophils.ConclusionOur results demonstrated that more neutrophils infiltration and overexpression of CEACAM1 were associated with poor clinical outcomes in TSCC tissues. Overexpression of CEACAM1 on tumor cells correlated with more neutrophils infiltration to some extent through upregulating mRNA expression of IL-8 and CXCL-6.

As a novel family of cell surface receptors, triggering receptors expressed on myeloid cells (TREMs) play an important role in inflammatory responses. However, the role of TREMs in the ocular immune system remains unknown. In this study, we examined the expression and function of TREM-1 in Pseudomonas aeruginosa keratitis, one of the most common sight-threatening ocular diseases. TREM-1 was significantly increased in human corneas after P. aeruginosa infection. Consistent with TREM-1 expression at the human ocular surface, TREM-1 levels (mRNA and protein) were also elevated in the infected corneas of C57BL/6 (B6) mice at 1, 3, and 5 days postinfection. To determine whether TREM-1 dictates the outcome of P. aeruginosa keratitis in susceptible mice, TREM-1 signaling in B6 mice was blocked with a soluble mTREM-1/Fc fusion protein. The results indicated that blockade of TREM-1 reduced the severity of corneal disease, polymorphonuclear neutrophil infiltration, Th1/proinflammatory cytokine expression and Toll-like receptor (TLR) activation but enhanced the production of Th2 cytokines, murine ␤-defensin 2 (mBD2), single Ig interleukin-1R-related molecule (SIGIRR), and ST2. Furthermore, we also used agonistic anti-mTREM-1 antibody to activate TREM-1 signaling in B6 mice and found that TREM-1 activation resulted in worsened disease and earlier corneal perforation in infected B6 mouse corneas and elevated production of proinflammatory cytokines and TLR signaling molecules but reduced expression of mBD2, SIGIRR, and ST2. To the best of our knowledge, this study provides the first evidence that TREM-1 functions as an inflammatory amplifier in P. aeruginosa keratitis by modulating TLR signaling and Th1/Th2 responses.