Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development

Dimitrova, Nadya; Gocheva, Vasilena; Bhutkar, Arjun; Resnick, Rebecca; Jong, Robyn M.; Miller, Kathryn; Bendor, Jordan; Jacks, Tyler

doi:10.1158/2159-8290.cd-15-0854

Cited by 127 publications

(130 citation statements)

References 45 publications

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“…Various studies and recent publications indicate that miR‐145 plays a role in cell proliferation, migration, and invasion in PCa and correlates with a high Gleason score, PSA, and bone metastasis . Other recent studies have shown that miR‐145 is involved with stromal‐related genes, as opposed to those related to the epithelium . In our study, miR‐145 expression could be from both cancer and stromal genes.…”

Section: Discussionsupporting

confidence: 62%

The association of let‐7c, miR‐21, miR‐145, miR‐182, and miR‐221 with clinicopathologic parameters of prostate cancer in patients diagnosed with low‐risk disease

Kurul¹,

Ateş

Yılmaz

et al. 2019

The Prostate

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Background The diagnostic benefit of prostate specific antigen (PSA) is limited, owing to its lack of specificity, particularly in men with PSA levels of 4.0 to 10.0 ng/mL. Therefore, there is a need for more specific and sensitive biomarkers to improve diagnostic accuracy and to predict prostate cancer (PCa) progression. Assessing the expression levels of specific microRNAs (miRNAs) in patients with PCa may be helpful in detecting cancer and predicting the cancer prognosis and its evolution, and may serve as markers to decide the treatment. We examined the expression levels of five miRNAs (let‐7c, miR‐21, miR‐145, miR‐185, and miR‐221) on patients with low‐risk PCa who had been eligible for active surveillance but underwent radical prostatectomy. We investigated the correlation between the relative expression of miRNAs and clinicopathologic parameters to evaluate their clinical significance. Materials and Methods Total RNA was isolated from the tumor and the corresponding non‐neoplastic prostate tissue of 45 patients who underwent radical prostatectomy. Quantitative reverse transcriptase‐polymerase chain reaction was used to measure the levels of let‐7c, miR‐21, miR‐145, miR‐185, miR‐221, and RNU6B expression, using TaqMan MicroRNA Assays. miRNA expression was examined in low‐risk PCa, and miRNAs' association with Gleason upgraded (GU) and biochemical recurrent (BR) patients was evaluated. Results We observed that miR‐21 and miR‐182 were overexpressed; conversely, let‐7c, miR‐145, and miR‐221 were underexpressed in patients with low‐risk PCa. GU patients (n = 16) and non‐upgraded patients (n = 28) were compared. miR‐145 was downregulated significantly in the GU group (P = 0.03). Similarly, miR‐221 was downregulated significantly in patients with BR (n = 14) compared with non‐recurrent patients (n = 30) (P = 0.04). Receiver operator characteristics (ROC) curve analysis revealed that miR‐221 levels were significantly associated with BR in patients with a cut‐off <−1.666, a value at which sensitivity was 70% and specificity 71% (area under curve [AUC] = 0.705, P = 0.030). Conclusions There is still a need for a tumor marker with higher sensitivity and specificity than that of PSA. Among the five miRNAs examined, miR‐221 was most associated with biochemical recurrence in low‐risk PCa.

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Section: Discussionsupporting

confidence: 62%

The association of let‐7c, miR‐21, miR‐145, miR‐182, and miR‐221 with clinicopathologic parameters of prostate cancer in patients diagnosed with low‐risk disease

Kurul¹,

Ateş

Yılmaz

et al. 2019

The Prostate

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“…Primary tumors were graded by a pathologist (R. Bronson) following established criteria (42), and only advanced (grades 3 and 4) tumors were used for the analysis. For the transplantation studies, 10 5 KP tumor cells (1233 line) (43) were injected via the lateral tail vein into mice or 5 × 10 5 KP tumor cells were injected s.c.…”

Section: Methodsmentioning

confidence: 99%

Quantitative proteomics identify Tenascin-C as a promoter of lung cancer progression and contributor to a signature prognostic of patient survival

Gocheva

Naba

Bhutkar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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119

130

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The extracellular microenvironment is an integral component of normal and diseased tissues that is poorly understood owing to its complexity. To investigate the contribution of the microenvironment to lung fibrosis and adenocarcinoma progression, two pathologies characterized by excessive stromal expansion, we used mouse models to characterize the extracellular matrix (ECM) composition of normal lung, fibrotic lung, lung tumors, and metastases. Using quantitative proteomics, we identified and assayed the abundance of 113 ECM proteins, which revealed robust ECM protein signatures unique to fibrosis, primary tumors, or metastases. These analyses indicated significantly increased abundance of several S100 proteins, including Fibronectin and Tenascin-C (Tnc), in primary lung tumors and associated lymph node metastases compared with normal tissue. We further showed that Tnc expression is repressed by the transcription factor Nkx2-1, a well-established suppressor of metastatic progression. We found that increasing the levels of Tnc, via CRISPR-mediated transcriptional activation of the endogenous gene, enhanced the metastatic dissemination of lung adenocarcinoma cells. Interrogation of human cancer gene expression data revealed that high TNC expression correlates with worse prognosis for lung adenocarcinoma, and that a three-gene expression signature comprising TNC, S100A10, and S100A11 is a robust predictor of patient survival independent of age, sex, smoking history, and mutational load. Our findings suggest that the poorly understood ECM composition of the fibrotic and tumor microenvironment is an underexplored source of diagnostic markers and potential therapeutic targets for cancer patients.

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“…It has been reported that stromal expression of miR-145 could promote neoangiogenesis in lung cancer development (5). miR-145 has also been suggested as one of the predictive factors for the early prediction of lymph node metastasis in patients with hepatocellular carcinoma (6).…”

Section: Disscussionmentioning

confidence: 99%

“…Both in vitro and in vivo studies have shown that miR-145 can significantly inhibit proliferation, migration and invasion in cancer cells (4). However, it has recently been found that tumor-specific deletion of miR-145 in an autochthonous mouse model of lung adenocarcinoma did not affect tumor development, and that stromal expression of miR-145 promotes neoangiogenesis in lung cancers (5), thus arguing against the delivery of this miRNA as an agent in cancer therapeutics. Moreover, miR-145 displays dramatic up-regulation in hepatocellular carcinoma and colorectal cancers with lymph node metastasis in comparison to those without lymph node metastasis (6, 7), suggesting that miR-145 may promote lymph node metastasis of cancer, or it may even play an oncogene role in metastatic cancer.…”

Section: Introductionmentioning

confidence: 99%

Role of STAT3 and FOXO1 in the Divergent Therapeutic Responses of Non-metastatic and Metastatic Bladder Cancer Cells to miR-145

Jiang

Huang

et al. 2017

Molecular Cancer Therapeutics

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Although miR-145 is the most frequently down-regulated miRNA in bladder cancer (BC), its exact stage-association and downstream effector have not been defined. Here, we found that miR-145 was upregulated in human BC patients with lymph node metastasis and in metastatic T24T cell line. Forced expression of miR-145 promoted anchorage-independent growth of T24T cells accompanied by the down-regulation of forkhead box class O1 (FOXO1). In contrast, in non-metastatic T24 cells, miR-145 overexpression inhibited cell growth with upregulation of FOXO1 and the knockdown of FOXO1 abolished the miR-145-mediated inhibition of cell growth. Mechanistic studies revealed that miR-145 directly bound to and attenuated 3′UTR activity of foxo1 mRNA in both T24 and T24T cells. Interestingly, miR-145 suppressed STAT3 phosphorylation at Tyr705 and increased foxo1 promoter transcriptional activity in T24 cells, but not in T24T cells, suggesting a role of STAT3 in the divergent responses to miR-145. Supporting this was our finding that STAT3 knockdown mimicked miR-145-mediated upregulation of FOXO1 in T24T cells and inhibition of anchorage-independent growth. Consistently, ectopic expression of miR-145 promoted tumor formation of xenograft T24T cells, whereas such promoting effect became inhibitory due to specific knockdown of STAT3. Together, our findings demonstrate the stage-specific association and function of miR-145 in BCs, and provide novel insights into the therapeutic targeting of miR-145.

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Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development

Cited by 127 publications

References 45 publications

The association of let‐7c, miR‐21, miR‐145, miR‐182, and miR‐221 with clinicopathologic parameters of prostate cancer in patients diagnosed with low‐risk disease

The association of let‐7c, miR‐21, miR‐145, miR‐182, and miR‐221 with clinicopathologic parameters of prostate cancer in patients diagnosed with low‐risk disease

Quantitative proteomics identify Tenascin-C as a promoter of lung cancer progression and contributor to a signature prognostic of patient survival

Role of STAT3 and FOXO1 in the Divergent Therapeutic Responses of Non-metastatic and Metastatic Bladder Cancer Cells to miR-145

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