MicroRNA-21 in cancer-associated fibroblasts supports lung adenocarcinoma progression.
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ABSTRACT:
SUBMITTER: Kunita A
PROVIDER: S-EPMC5995955 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionPancreatic ductal adenocarcinoma (PDAC) is projected to rise to the second leading cause of U.S. cancer-related deaths by 2020. Novel therapeutic targets are desperately needed. MicroRNAs (miRs) are small noncoding RNAs that function by suppressing gene expression and are dysregulated in cancer. miR-21 is overexpressed in PDAC tumor cells (TC) and is associated with decreased survival, chemoresistance and invasion. Dysregulation of miR regulatory networks in PDAC tumor-associated fibroblasts (TAFs) have not been previously described. In this study, we show that miR-21 expression in TAFs promotes TC invasion.MethodsIn-situ hybridization for miR-21 was performed on the 153 PDAC patient UCLA tissue microarray and 23 patient-matched lymph node metastases. Stromal and TC histoscores were correlated with clinicopathologic parameters by univariate and multivariate Cox regression. miR-21 positive cells were further characterized by immunofluorescence for mesenchymal/epithelial markers. For in vitro studies, TAFs were isolated from freshly resected human PDAC tumors by the outgrowth method. miR-21 was overexpressed/inhibited in fibroblasts and then co-cultured with GFP-MiaPaCa TCs to assess TC invasion in modified Boyden chambers.ResultsmiR-21 was upregulated in TAFs of 78% of tumors, and high miR-21 significantly correlated with decreased overall survival (P = 0.04). Stromal miR-21 expression was also significantly associated with lymph node invasion (P = 0.004), suggesting that it is driving TC spread. Co-immunofluorescence revealed that miR-21 colocalized with peritumoral fibroblasts expressing ?-smooth muscle actin. Moreover, expression of miR-21 in primary TAFs correlated with miR-21 in TAFs from patient-matched LN metastases; evidence that PDAC tumor cells induce TAFs to express miR-21. miR-21 expression in TAFs and TCs promotes invasion of TCs and is inhibited with anti-miR-21.ConclusionsmiR-21 expression in PDAC TAFs is associated with decreased overall survival and promotes TC invasion. Anti-miR-21 may represent a novel therapeutic strategy for dual targeting of both tumor and stroma in PDAC.
| S-EPMC3750050 | biostudies-literature
Project description:The present study aimed to investigate the roles of cancer-associated fibroblasts (CAFs), matrix metalloproteinase-9 (MMP-9) and lymphatic vessel density (LVD) during the progression from adenocarcinoma in situ (AIS) to invasive lung adenocarcinoma (IAC). A total of 77 patients with stage 0-IA lung adenocarcinoma were enrolled. The expression levels of ?-smooth muscle actin, MMP-9 and D2-40 were immunohistochemically analyzed. Survival analysis was performed using the Kaplan-Meier method. In the non-invasive component, the proportion of CAFs and the expression levels of MMP-9 increased from AIS to IAC; however, the LVD was not significantly different. CAFs were positively correlated with levels of MMP-9. The LVD had no significant correlation with CAFs and MMP-9. In the invasive component, CAFs, MMP-9 and LVD were significantly higher in IAC compared with in minimally invasive adenocarcinoma. CAFs, MMP-9 and LVD were all positively correlated with each other. The micropapillary subtype in IAC was associated with overall survival (OS). The LVD in IAC, but not MMP-9 and CAFs, was associated with OS. CAFs, MMP-9 and LVD were involved in the progression from AIS to IAC. CAFs exhibited a strong association with MMP-9 levels in the non-invasive and invasive components. The increase in the proportion of CAFs and the expression levels of MMP-9 may have been an early event before the adenocarcinoma became invasive. Once the adenocarcinoma was invasive, the LVD served an important role in tumor invasion and metastasis, and hence may be used as a prognostic marker of poor OS in stage IA IAC.
| S-EPMC7471727 | biostudies-literature
Project description:The development and progression of lung adenocarcinoma, one of the most common cancers, is driven by the interplay of genetic and epigenetic changes and the role of chromatin structure in malignant transformation remains poorly understood. We used systematic nucleosome distribution and chromatin accessibility microarray mapping platforms to analyze the genome-wide chromatin structure from normal tissues and from primary lung adenocarcinoma of different grades and stages. We identified chromatin-based patterns across different patients with lung adenocarcinoma of different cancer grade and stage. Low-grade cancers had nucleosome distributions very different compared with the corresponding normal tissue but had nearly identical chromatin accessibility. Conversely, nucleosome distributions of high-grade cancers showed few differences. Substantial disruptions in chromosomal accessibility were seen in a patient with a high-grade and high-stage tumor. These data imply that chromatin structure changes during the progression of lung adenocarcinoma. We have therefore developed a model in which low-grade lung adenocarcinomas are linked to changes in nucleosome distributions, whereas higher-grade tumors are linked to large-scale chromosomal changes. These results provide a foundation for the development of a comprehensive framework linking the general and locus-specific roles of chromatin structure to lung cancer progression. We propose that this strategy has the potential to identify a new class of chromatin-based diagnostic, prognostic and therapeutic markers in cancer progression.
| S-EPMC3680533 | biostudies-other
Project description:Metabolic reprogramming of the tumor microenvironment is recognized as a cancer hallmark. To identify new molecular processes associated with tumor metabolism, we analyzed the transcriptome of bulk and flow-sorted human primary non-small cell lung cancer (NSCLC) together with 18FDG-PET scans, which provide a clinical measure of glucose uptake. Tumors with higher glucose uptake were functionally enriched for molecular processes associated with invasion in adenocarcinoma and cell growth in squamous cell carcinoma (SCC). Next, we identified genes correlated to glucose uptake that were predominately overexpressed in a single cell-type comprising the tumor microenvironment. For SCC, most of these genes were expressed by malignant cells, whereas in adenocarcinoma, they were predominately expressed by stromal cells, particularly cancer-associated fibroblasts (CAF). Among these adenocarcinoma genes correlated to glucose uptake, we focused on glutamine-fructose-6-phosphate transaminase 2 (GFPT2), which codes for the glutamine-fructose-6-phosphate aminotransferase 2 (GFAT2), a rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP), which is responsible for glycosylation. GFPT2 was predictive of glucose uptake independent of GLUT1, the primary glucose transporter, and was prognostically significant at both gene and protein level. We confirmed that normal fibroblasts transformed to CAF-like cells, following TGF? treatment, upregulated HBP genes, including GFPT2, with less change in genes driving glycolysis, pentose phosphate pathway, and TCA cycle. Our work provides new evidence of histology-specific tumor stromal properties associated with glucose uptake in NSCLC and identifies GFPT2 as a critical regulator of tumor metabolic reprogramming in adenocarcinoma.Significance: These findings implicate the hexosamine biosynthesis pathway as a potential new therapeutic target in lung adenocarcinoma. Cancer Res; 78(13); 3445-57. ©2018 AACR.
| S-EPMC6030462 | biostudies-literature
Project description:Age is a major risk factor for the development of cancer. Senescent fibroblasts, which accumulate with age, secrete protumorigenic factors collectively referred to as the senescence-associated secretory phenotype (SASP). Here, we examined the molecular mechanisms that control SASP activation, focusing on the known SASP factor osteopontin (OPN). We found that expression of the canonical SASP members interleukin (IL)-6 and IL-8, but not OPN, were dependent upon a persistent DNA damage response (DDR) as evidenced by ATM and NF-?B activation. Treatment with several histone deacetylase (HDAC) inhibitors robustly activated SASP in the absence of DNA breaks, suggesting that DDR-dependent SASP activation occurs in response to chromatin remodeling rather than physical breaks in DNA. In the setting of HDAC inhibition, IL-6 and IL-8 expression remained dependent upon ATM and NF-?B, while OPN expression remained independent of these factors. Further analysis revealed that HDAC1 inhibition was sufficient to induce OPN expression, which is interesting given that loss of HDAC1 expression correlates with increased OPN expression within the stromal compartment of invasive breast cancers. Importantly, fibroblasts treated with HDAC inhibitors promoted tumor growth in vivo. Our findings therefore indicate that HDAC modulation plays an important role in stromal cell activation, with important implications for the use of HDAC inhibitors in the treatment of cancer.
| S-EPMC3605047 | biostudies-literature
Project description:ObjectiveSmall-cell lung cancer (SCLC) is aggressive, with early metastasis. Cytokines secreted by cancer-associated fibroblasts (CAFs) within various tumors influences these features, but the function in particular of TGFβ1 (transforming growth factor beta 1) is controversial and unknown in SCLC. This study explored the influence of TGFβ1 in CAFs on the development, immune microenvironment, and radiotherapy sensitivity of SCLC.MethodsSCLC specimens were collected from 90 patients who had received no treatment before surgery. Tumor and tumor stroma were subjected to multiplex immunohistochemistry to quantitate TGFβ1 and other immune factors in CAFs. Cell proliferation and flow cytometry apoptosis assays were used to investigate associations between TGFβ1 and proliferation and radiotherapy sensitivity. The immune factors in tumors were detected by immunohistochemistry in vitro and in vivo (mice).ResultsTGFβ1 levels on CAFs lower or higher than the median were found, respectively, in 52.2 and 47.8% of patients; overall survival of patients with TGFβ1-high levels (53.9 mo) was significantly longer than that of the TGFβ1-low group (26.9 mo; P = 0.037). The univariate and multivariate analyses indicated that a TGFβ1-high level was an independent predictor of increased survival time. TGFβ1-high levels in CAFs were associated with inhibition of growth, proliferation, antitumor immunity, and enhanced radiotherapeutic sensitivity and tumor immunity of tumor. TGFβ1-low levels promoted tumor cell growth and radiotherapy sensitivity in vivo and in vitro.ConclusionHigh levels of TGFβ1 in CAFs were associated with longer overall survival in patients with SCLC and enhanced radiotherapy sensitivity.
| S-EPMC8172974 | biostudies-literature
Project description:In this study we evaluated the interaction of pancreatic cancer cells, cancer-associated fibroblasts, and distinct drugs such as ?-cyano-4-hydroxycinnamate, metformin, and gemcitabine. We observed that ?-cyano-4-hydroxycinnamate as monotherapy or in combination with metformin could significantly induce collagen I deposition within the stromal reaction. Subsequently, we demonstrated that cancer-associated fibroblasts impaired the anti-proliferation efficacy of ?-cyano-4-hydroxycinnamate, metformin and gemcitabine. Interestingly, inhibition of autophagy in these fibroblasts can augment the anti-proliferation effect of these chemotherapeutics in vitro and can reduce the tumor weight in a syngeneic pancreatic cancer model. These results suggest that inhibiting autophagy in cancer-associated fibroblasts may contribute to strategies targeting cancer.
| S-EPMC6290725 | biostudies-literature
Project description:Gamma-glutamyltransferase 5 (GGT5) is a member of the gamma-glutamyl transpeptidase gene family with the capacity of cleaving the gamma-glutamyl moiety of glutathione, but its role in cancer progression has never been revealed. In this study, we found that gene GGT5 was highly expressed in cancer-associated fibroblasts (CAFs) in lung adenocarcinoma, predicting the unfavorable survival of patients with lung adenocarcinoma. Cell growth, foci formation and spheres formation analyses showed that cancer cell proliferation was attenuated under treatment with the conditioned media from GGT5-silenced CAFs. Moreover, high expression of GGT5 in CAFs enhanced the drug resistance of cancer cells by increasing intracellular glutathione and reducing the intracellular reactive oxygen species in cancer cells. In mouse xenograft model, we proved that targeting GGT5 with a small-molecule inhibitor GGsTop could inhibit tumor growth and increase the chemosensitivity of cancer cells. Taken together, our study illuminates that high level of GGT5 in CAFs contributes to cancer cell survival and drug resistance, indicating that GGT5 may be a promising therapeutic target in lung adenocarcinoma.
| S-EPMC7377883 | biostudies-literature
Project description:Immunoglobulin (CD79a) binding protein 1 (IGBP1) is universally overexpressed in lung adenocarcinoma and exerts an anti-apoptotic effect by binding to PP2Ac. However, the molecular mechanism of IGBP1 overexpression is still unclear. In the present study, we used a microRNA (miRNA) array and TargetScan Human software to detect IGBP1-related miRNAs that regulate IGBP1 expression. The miRNA array analysis revealed more than 100 miRNAs that are dysregulated in early invasive adenocarcinoma. On the other hand, in silico analysis using TargetScan Human revealed 79 miRNAs that are associated with IGBP1 protein expression. Among the miRNAs selected by miRNA array analysis, six (miR-34b, miR-138, miR-374a, miR-374b, miR-1909, miR-3941) were also included among those selected by TargetScan analysis. Real-time reverse transcription PCR (real-time RT-PCR) showed that the six microRNAs were downregulated in invasive adenocarcinoma (IGBP1+) relative to adjacent normal lung tissue (IGBP1-). Among these microRNAs, only miR-34b and miR-3941 depressed luciferase activity by targeting 3'UTR-IGBP1 in the luciferase vector. We transfected miR-34b and miR-3941 into lung adenocarcinoma cell lines (A549, PC-9), and both of them suppressed IGBP1 expression and cell proliferation. Moreover, the transfected miR-34b and miR-3941 induced apoptosis of a lung adenocarcinoma cell line, similarly to the effect of siIGBP1 RNA. As well as miR-34b, we found that miR-3941 targeted IGBP1 specifically and was able to exclusively downregulate IGBP1 expression. These findings indicate that suppression of miR-3941 has an important role in the progression of lung adenocarcinoma at an early stage.
| S-EPMC5378261 | biostudies-literature
Project description:BackgroundHepatocellular carcinoma (HCC) remains a global challenge due to its high morbidity and mortality rates as well as poor response to treatment. The communication between tumor-derived elements and stroma plays a critical role in facilitating cancer progression of HCC. Exosomes are small extracellular vesicles (EVs) that are released from the cells upon fusion of multivesicular bodies with the plasma membrane. There is emerging evidence indicating that exosomes play a central role in cell-to-cell communication. Much attention has been paid to exosomes since they are found to transport bioactive proteins, messenger RNA (mRNAs) and microRNA (miRNAs) that can be transferred in active form to adjacent cells or to distant organs. However, the mechanisms underlying such cancer progression remain largely unexplored.MethodsExosomes were isolated by differential ultracentrifugation from conditioned medium of HCC cells and identified by electron microscopy and Western blotting analysis. Hepatic stellate cells (HSCs) were treated with different concentrations of exosomes, and the activation of HSCs was analyzed by Western blotting analysis, wound healing, migration assay, Edu assay, CCK-8 assay and flow cytometry. Moreover, the different miRNA levels of exosomes were tested by real-time quantitative PCR (RT-PCR). The angiogenic ability of activated HSCs was analyzed by qRT-PCR, CCK-8 assay and tube formation assay. In addition, the abnormal lipid metabolism of activated HSCs was analyzed by Western blotting analysis and Oil Red staining. Finally, the relationship between serum exosomal miRNA-21 and prognosis of HCC patients was evaluated.ResultsWe showed that HCC cells exhibited a great capacity to convert normal HSCs to cancer-associated fibroblasts (CAFs). Moreover, our data revealed that HCC cells secreted exosomal miRNA-21 that directly targeted PTEN, leading to activation of PDK1/AKT signaling in HSCs. Activated CAFs further promoted cancer progression by secreting angiogenic cytokines, including VEGF, MMP2, MMP9, bFGF and TGF-β. Clinical data indicated that high level of serum exosomal miRNA-21 was correlated with greater activation of CAFs and higher vessel density in HCC patients.ConclusionsIntercellular crosstalk between tumor cells and HSCs was mediated by tumor-derived exosomes that controlled progression of HCC. Our findings provided potential targets for prevention and treatment of live cancer.
| S-EPMC6307162 | biostudies-literature