Osteopontin (OPN) plays an important functional role in both physiologic and pathologic states. OPN is implicated in the progression of fibrosis, cancer, and metastatic disease in several organ systems. The epithelial-mesenchymal transition (EMT), first described in embryology, is increasingly being recognized as a significant contributor to fibrotic phenotypes and tumor progression. Several well-established transcription factors regulate EMT and are conserved across tissue types and organ systems, including TWIST, zinc finger E-box-binding homeobox (ZEB), and SNAIL-family members. Recent literature points to an important relationship between OPN and EMT, implicating OPN as a key regulatory component of EMT programs. In this review, OPN’s interplay with traditional EMT activators, both directly and indirectly, will be discussed. Also, OPN’s ability to restructure the tissue and tumor microenvironment to indirectly modify EMT will be reviewed. Together, these diverse pathways demonstrate that OPN is able to modulate EMT and provide new targets for directing therapeutics.
Osteopontin (OPN) promotes hepatic fibrosis, and developing therapies targeting OPN expression in settings of hepatic injury holds promise. The polyphenol epigallocatechin-3-gallate (EGCG), found in high concentrations in green tea, downregulates OPN expression through OPN mRNA degradation, but the mechanism is unknown. Previous work has shown that microRNAs can decrease OPN mRNA levels, and other studies have shown that EGCG modulates the expression of multiple microRNAs. In our study, we first demonstrated that OPN induces hepatic stellate cells to transform into an activated state. We then identified three microRNAs which target OPN mRNA: miR-181a, miR-10b, and miR-221. In vitro results show that EGCG upregulates all three microRNAs, and all three microRNAs are capable of down regulating OPN mRNA when administered alone. Interestingly, only miR-221 is necessary for EGCG-mediated OPN mRNA degradation and miR-221 inhibition reduces the effects of EGCG on cell function. In vivo experiments show that thioacetamide (TAA)-induced cell cytotoxicity upregulates OPN expression; treatment with EGCG blocks the effects of TAA. Furthermore, chronic treatment of EGCG in vivo upregulates all three microRNAs equally, suggesting that in more chronic treatment all three microRNAs are involved in modulating OPN expression. We conclude that in in vitro and in vivo models of TAA-induced hepatic fibrosis, EGCG inhibits OPN-dependent injury and fibrosis. EGCG works primarily by upregulating miR-221 to accelerate OPN degradation. EGCG may therefore have utility as a protective agent in settings of liver injury.
Introduction Osteopontin (OPN) mediates metastasis and invasion of hepatocellular carcinoma (HCC). Epigallocatechin-3-gallate (EGCG), found in green tea, suppresses HCC tumor growth in vitro. We sought to investigate the role of EGCG in modulating OPN in cell lines of metastatic HCC. Methods Experimental HCC cell lines included HepG2 and MHCC-97H HCC cells, which express high levels of OPN, and the Hep3B cells, which express lesser levels of OPN. Cells were treated with EGCG (0.02–20 μg/mL) before measurement of OPN with enzyme-linked immunosorbent assay and reverse transcriptase-polymerase chain reaction. Scratch assay measured cell migration. Binding of the OPN promoter to RNA pol II was evaluated by the use of Chromatin-IP assay after EGCG treatment. Transcriptional regulation of OPN was investigated with luciferase reporter plasmids containing various deletion fragments of the human OPN promoter. Measurement of the half-life of OPN mRNA was conducted using actinomycin D. Results Treatment of MHCC-97H and HepG2 cells with 2 μg/mL and 20 μg/mL EGCG caused a ~6-fold and ~90-fold decrease in secreted protein levels of OPN (All P < .001). OPN mRNA was decreased with EGCG concentrations of 0.2–20 μg/ml (All P < .001). The 3-(4, 5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (ie, MTT) assay revealed that differences in OPN expression were not due to viability of the HCC cell lines. Promoter assay and chromatin immunoprecipitation analysis revealed no effect of EGCG on the transcriptional regulation of OPN. Posttranscriptionally, EGCG decreased the half-life of OPN mRNA from 16.8 hours (95% confidence interval 9.0–125.1) to 2.5 hours (95% confidence interval 2.1–3.2) (P < .001). Migration was decreased in EGCG treated cells at 24 hours (8.0 ± 2.4% vs 21.2 ± 10.8%, P < .01) and at 48 hours (13.2 ± 3.6% vs 53.5 ± 19.8%, P < .001). Conclusion We provide evidence that EGCG decreases OPN mRNA and secreted OPN protein levels by decreasing the half-life of OPN mRNA in MHCC-97H cells. The translatability of EGCG for patients with HCC is promising, because EGCG is an inexpensive, easily accessible chemical with an extensive history of safety.
ObjectiveAlthough dermatologists strive to provide patient education on sun protection and skin cancer, approximately 90% of Americans have limited health literacy skills. Little has been written about the means to best teach all levels of learners to recognize common benign and malignant skin lesions. Earlier work found that with advancing age, adults were less able to identify concerning lesions, thus underscoring the need for accessible education.MethodsWe showed subjects a brief video (7th grade level) about common cutaneous growths, reducing the risk of skin cancer, and the importance of early detection. Subjects were asked about their skin cancer history, educational format preference, and the perceived impact of the video. Comprehension of symptoms of skin cancer and the benefits of sunscreen use and the ability to identify a melanoma, nevus, angioma, and seborrheic keratosis were also assessed.ResultsOf the 156 subjects, mean age 52.7 years (range, 18-88 years), 31% had a history of skin cancer. A total of 98.7% found the video to be helpful; 92% preferred having a video as part of their teaching versus 9% who preferred written materials alone, 99% knew that a new or changing lesion could signal skin cancer, and 100% correctly answered that wearing sunscreen is protective. Subjects correctly identified lesions as melanoma (99%), benign mole (97%), angiomas (96%), and seborrheic keratosis (91%). There was a nominal trend toward higher scores in people who preferred video learning, had no history of skin cancer, and were older than 60 years of age.ConclusionIn this study, we found that a brief, plain-language video was effective at conveying understandable content to help subjects learn to identify common cancerous and benign skin growths while also teaching them strategies to protect against skin cancer.
eratinocyte carcinoma (KC), also known as nonmelanoma skin cancer, refers to basal cell carcinoma and squamous cell carcinoma. The incidence rates of KC are much lower among people with skin of color compared with people who identify as non-Hispanic White. 1 However, KCs in individuals with skin of color can be associated with worse outcomes owing to a higher risk for tumor invasion, metastasis, atypical clinical presentations, and delays in diagnosis compared with non-Hispanic White populations. 2 Ultraviolet exposure is the strongest modifiable risk factor associated with KC, but studies establishing this association have been primarily in non-Hispanic White populations. To date, and to our knowledge, there has been no comprehensive systematic review examining the association between UV exposure and KC among individuals with skin of color. Methods Personnel, Protocol, and RegistrationThe systematic review team included 5 reviewers (E.K., F.C.P.S.L., M.A., J.P., and A.S.A.) and 1 health sciences librarian (R.B.) from the University of Texas Libraries. The systematic review was registered on March 8, 2021, in the PROSPERO database (CRD42021234735). We used the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. This research project was considered by The University of Texas at Austin Institutional Review Board as non-human participant research, and approval was not required.IMPORTANCE Ultraviolet radiation exposure is an important modifiable risk factor for keratinocyte carcinoma (KC) in fair-skinned non-Hispanic White populations; however, the evidence for this relationship in darker-skinned populations is less certain.OBJECTIVE To assess and synthesize the published data concerning the association between UV exposure and the risk of KC in individuals with skin of color.EVIDENCE REVIEW PubMed, Cochrane, and Web of Science databases were searched from database origin through January 2022. Studies deemed eligible included UV exposure as a risk factor for KC in individuals with skin of color, defined as any race other than non-Hispanic White, Fitzpatrick skin types IV to VI, or tanning ability of rarely or never burns. The UV index, irradiance, latitude, history of phototherapy, history of sunburn, or occupational exposure were used as measures of exposure. The Oxford Centre for Evidence-Based Medicine guidelines were used to assess evidence quality.FINDINGS A total of 72 716 articles appeared in the search. After duplicate removal, 29 393 database records were screened, 454 full-text articles were assessed, a forward and reverse citation search was performed, and 12 articles, with clinical data spanning the years 1990 to 2019, met inclusion criteria. More than 32 970 KCs in individuals with skin of color were included. Eight studies found no association between UV exposure and KC, while 4 studies showed a positive association. Study types included 1 ecological study, 9 cohort studies, and 2 case-control studies. The quality of the studies was rated from moderate to low...
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