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Transforming Growth Factor β (TGF-β) is one of the most common secretory proteins which are recognized by membrane receptors joined to transcription regulatory factor. TGF-β signals are transduced by the Smads family that regulate differentiation, proliferation, early growth, apoptosis, homeostasis, and tumor development. Functional study of TGF-β signaling pathway and Smads role is vital for certain diseases such as cancer. Alternative splicing produces a diverse range of protein isoforms with unique function and the ability to react differently with various pharmaceutical products. This review organizes to describe the general study of Smads family, the process of alternative splicing, the general aspect of alternative splicing of Smad4 in cancer and the possible use of spliceoforms for the diagnosis and therapeutic purpose. The main aim and objective of this article are to highlight some particular mechanisms involving in alternatives splicing of cancer and also to demonstrate new evidence about alternative splicing in different steps given cancer initiation and progression.

Osteoarthritis (OA) is the most common degenerative disease affecting the joints, and inflammation appears to play a critical role in the initiation and progression of OA. Caffeic acid phenethyl ester (CAPE), a natural flavonoid compound, has anti-inflammatory and antioxidant functions. However, its anti-inflammatory effects on OA and the underlying mechanisms of action of CAPE in the treatment of OA remain elusive. Therefore, the present study investigated the anti-inflammatory effects of CAPE on IL-1β-stimulated chondrocytes in vitro and surgically induced rat models of OA in vivo. In vitro, CAPE reduced the expression of inducible nitric oxide synthase and cyclooxygenase-2 in IL-1β-stimulated chondrocytes, as well as the extracellular secretion of nitric oxide and prostaglandin E2 in the cell culture supernatants. In addition, CAPE attenuated the degradation of extracellular matrix by increasing the expression of aggrecan and collagen II, and decreasing the expression of MMP3, MMP13 and a disintegrin and metalloproteinase with thrombospondin motif-5. Furthermore, CAPE attenuated NF-κB signaling and activated the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signaling pathway in IL-1β-stimulated chondrocytes. In vivo, CAPE protected cartilage from destruction and delayed the progression of OA in rats. Taken together, the findings of the present study indicated that CAPE may be a potential therapeutic agent for the prevention or treatment of OA.

Migration and metastasis of tumor cells greatly contributes to the failure of cancer treatment. Recently, the extracellular protein secreted protein acidic and rich in cysteine (SPARC) has been reported closely related to tumorigenesis. Some articles have suggested that SPARC promoted metastasis in several highly metastatic tumors. However, there are also some studies shown that SPARC acted as an antitumor factor. SPARC-induced epithelial-tomesenchymal transition (EMT) in melanoma cells and promoted EMT in hepatocellular carcinoma. Therefore, the role of SPARC in tumorigenesis and its relationship with EMT is still unclear. In this study, we investigated the expression change of SPARC in A549 and H1299 lung cancer cells undergoing EMT process. Our study indicated that SPARC was upregulated in A549 and H1299 cells EMT process. We further investigated the function of SPARC on proliferation, migration, and EMT process of A549 and H1299 cells. Overexpression of SPARC promoted the migration and EMT of A549 and H1299 cells. Knockdown SPARC inhibited the EMT of A549 cells. Overexpression of SPARC induced the increased expression of p-Akt and P-ERK. Furthermore, exogenous SPARC peptide promoted transforming growth factor (TGF)-β1-induced EMT of A549 and H1299 cells. SPARC knockdown partially eliminated TGF-β1 function in inducing EMT of A549 cells. SPARC follistatin-like functional domain reduced the expression of E-cadherin, but had no effect on the expression of p-Akt and p-ERK. In conclusion, we elucidated that SPARC contributes to tumorigenesis by promoting migration and EMT of A549 and H1299 lung cancer cells. These results will provide some new suggestion for lung cancer treatment. © 2018 BioFactors, 44(5):453-464, 2018Abbreviations: A549, A human lung adenocarinoma epithelial cell line; Akt, A serine/threonine-specific protein kinase; BSA, bovine serum albumin; CCK-8, cell counting kit-8; DMEM, Dulbecco's modified Eagle's Medium; EC, extracellular calcium-binding domain; EDTA, ethylenediaminetetraacetic acid; EGFP, enhancer green fluorescent protein; EGF, epidermal growth factor; EMT, epithelial-to-mesenchymal transition; ERK, extracellular signal-regulated kinases; FBS, fetal bovine serum; FS, follistatin-like functional domain; Fyn, Fyn proto-oncogene, Src family tyrosine kinase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; H1299, A human non-small cell lung carcinoma cell line; ILK, integrin-linked kinase; MDM2, mouse double minute 2 homolog; NF-κB, nuclear factor kappa B subunit 1; Nab-PTX, nanoparticle albumin bound paclitaxel; NSCLC, nonsmall cell lung cancer; NT, N terminal acidic domain; PBS, phosphate-buffered saline; PARP, poly (ADP-ribose) polymerase 1; PMSF, phenylmethane sulfonyl fluoride; RIPA, radioimmunoprecipitation assay buffer; SDS, sodium dodecyl sulfate; SPARC, secreted protein acidic and rich in cysteine; TGF-β, transforming growth factor; TBST, a mixture of tris-buffered saline and Tween 20 Additional Supporting Information may be found in the online version of this article.

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Mdm2 is a well studied oncogene and has been reported to be closely related to chemoresistance in different manners. In this article, we discuss the current knowledge of mdm2's function in drug resistance, the novel relationship between MDM2 and Akt phosphorylation, the role of Akt signaling pathway in epithelial-mesenchymal transition, and the positive correlation among MDM2, epithelial-mesenchymal transition and drug resistance. We propose a possible pathway by which MDM2 increases drug resistance through inducing epithelial-mesenchymal transition independent of p53. This pathway may play a significant role in the tumorigenesis and chemoresistance. By targeting MDM2, we can re-activate the function of p53, inhibit the epithelial-mesenchymal transition process and thus increase cancer cells sensitivity to chemotherapy. Thus, from p53-dependent and p53-independent aspects, it may present a better strategy for cancer treatment than targeting other genes.

Background Cold-inducible RNA binding protein (CIRP) is a newly discovered proto-oncogene. In this study, we investigated the role of CIRP in the progression of non-small cell lung cancer (NSCLC) using patient tissue samples, cultured cell lines and animal lung cancer models. Methods Tissue arrays, IHC and HE staining, immunoblotting, and qRT-PCR were used to detect the indicated gene expression; plasmid and siRNA transfections as well as viral infection were used to manipulate gene expression; cell proliferation assay, cell cycle analysis, cell migration and invasion analysis, soft agar colony formation assay, tail intravenous injection and subcutaneous inoculation of animal models were performed to study the role of CIRP in NSCLC cells; Gene expression microarray was used to select the underlying pathways; and RNA immunoprecipitation assay, biotin pull-down assay, immunopurification assay, mRNA decay analyses and luciferase reporter assay were performed to elucidate the mechanisms. The log-rank (Mantel-Cox) test, independent sample T-test, nonparametric Mann-Whitney test, Spearman rank test and two-tailed independent sample T-test were used accordingly in our study. Results Our data showed that CIRP was highly expressed in NSCLC tissue, and its level was negatively correlated with the prognosis of NSCLC patients. By manipulating CIRP expression in A549, H460, H1299, and H1650 cell lines, we demonstrated that CIRP overexpression promoted the transition of G1/G0 phase to S phase and the formation of an enhanced malignant phenotype of NSCLC, reflected by increased proliferation, enhanced invasion/metastasis and greater tumorigenic capabilities both in vitro and in vivo. Transcriptome sequencing further demonstrated that CIRP acted on the cell cycle, DNA replication and Wnt signaling pathway to exert its pro-oncogenic action. Mechanistically, CIRP directly bound to the 3′- and 5′-UTRs of CTNNB1 mRNA, leading to enhanced stability and translation of CTNNB1 mRNA and promoting IRES-mediated protein synthesis, respectively. Eventually, the increased CTNNB1 protein levels mediated excessive activation of the Wnt/β-catenin signaling pathway and its downstream targets C-myc, COX-2, CCND1, MMP7, VEGFA and CD44. Conclusion Our results support CIRP as a candidate oncogene in NSCLC and a potential target for NSCLC therapy.