Hepatocyte growth factor is predominantly expressed by the carcinoma cells in non–small-cell lung cancer

Tsao, Ming‐Sound; Yang, Yaping; Marcus, Alexander; Liu, Geoffrey; Mou, Lun-jun

doi:10.1053/hupa.2001.21133

Cited by 42 publications

(31 citation statements)

References 33 publications

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“…S4A), confirming the HGF-dependent regulation of miR-519c in human tumors. Moreover, consistent with a previous study (27), expression of HGF was predominantly in the lung tumor cells, with a significantly lower expression level in the surrounding stroma cells (Supplementary Fig. S4B), indicating that HGF regulates miR-519c mainly through an autocrine manner in lung cancer.…”

Section: δ3′utrsupporting

confidence: 91%

MicroRNA-519c Suppresses Hypoxia-Inducible Factor-1α Expression and Tumor Angiogenesis

Ting

Chen²,

Johansson³

et al. 2010

Cancer Research

186

113

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Hypoxia-inducible factor-1α (HIF-1α) is widely considered to be one of the key regulators of tumor angiogenesis. The upstream regulation is complex and involves several growth factors, cytokines, and hypoxia. Herein, we have identified miR-519c as a hypoxia-independent regulator of HIF-1α, acting through direct binding to the HIF-1α 3′ untranslated region and leading to reduced tumor angiogenesis. Overexpression of miR-519c resulted in a significant decrease of HIF-1α protein levels and reduced the tube formation of human umbilical vein endothelial cells; similarly, antagomir inhibition of miR-519c increased the level of HIF-1α protein and enhanced angiogenic activity, suggesting an important role of miR-519c in HIF-1α-mediated angiogenesis. Consistent with the overexpression of miR-519c in cancer patients with better prognosis, mice injected with miR-519c-overexpressing cells exhibited dramatically reduced HIF-1α levels, followed by suppressed tumor angiogenesis, growth, and metastasis. In addition, we found that hepatocyte growth factor (HGF), a known HIF-1α inducer, reduced the miR-519c levels through an Akt-dependent pathway. This regulation was posttranscriptional and may be mediated by suppression of miR-519c maturation. Taken together, our findings provide the first evidence that miR-519c is a pivotal regulator of tumor angiogenesis and that microenvironmental HGF contributes to regulating miR-519c biogenesis in cancer cells. Cancer Res; 70(7); 2675-85. ©2010 AACR.

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Section: δ3′utrsupporting

confidence: 91%

MicroRNA-519c Suppresses Hypoxia-Inducible Factor-1α Expression and Tumor Angiogenesis

Ting

Chen²,

Johansson³

et al. 2010

Cancer Research

186

113

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“…Our studies would predict that clinical trials of Met inhibitors, such as PHA-665752, in MPM would be most effective in patients whose tumors express both Met and HGF. Furthermore, PHA-665753 treatment may also be effective in other tumor types that exhibit autocrine HGF production, such as some non -small cell lung carcinomas (54).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Met Receptor in Mesothelioma

Mukohara

Civiello

Davis

et al. 2005

Clinical Cancer Research

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Background: Expression of the Met receptor and its ligand, hepatocyte growth factor (HGF), has been observed in 74% to100% and 40% to 85% of malignant pleural mesothelioma (MPM) specimens, respectively. HGF stimulation has been shown to enhance MPM cell proliferation, migration, cell scattering, and invasiveness. Experimental Design: To investigate a potential therapeutic role for the Met receptor in MPM, we examined the effects of PHA-665752, a specific small-molecule inhibitor of the Met receptor tyrosine kinase, in a panel of 10 MPM cell lines. Results: Two of the cell lines, H2461and JMN-1B, exhibited autocrine HGF production as measured by ELISA (3.9 and 10.5 ng/mL, respectively, versus <0.05 ng/mL in other cell lines). Evaluation of PHA-665752 across the 10 MPM cell lines indicated that despite Met expression in all cell lines, only in cell lines that exhibited a Met/HGF autocrine loop, H2461 and JMN-1B, did PHA-665752 inhibit growth with an IC 50 of 1 and 2 Amol/L, respectively. No activating mutations in Met were detected in any of the cell lines. Consistent with observed growth inhibition, PHA-665752 caused cell cycle arrest at G 1 -S boundary accompanied by a dose-dependent decrease in phosphorylation of Met, p70S6K, Akt, and extracellular signal-regulated kinase 1/2. Growth of H2461 cells was also inhibited by neutralizing antibodies to HGF and by RNA interference knockdown of the Met receptor, confirming that growth inhibition observed was through a Metdependent mechanism. PHA-665752 also reduced MPM in vitro cell migration and invasion. Conclusions: Taken together, these findings suggest that inhibition of the Met receptor may be an effective therapeutic strategy for patients with MPM and provides a mechanism, the presence of a HGF/Met autocrine loop, by which to select patients for PHA-665752 treatment.

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“…Discussion HGF has been described as having tumorigenetic, vascularizing, and motogenic effects on human lung cancer, both in vitro and in vivo, and to have prognostic implications in patients with non-small cell lung carcinoma. [1][2][3][4][5][6][7][8][9][10][11] Although many reports suggest that HGF is produced by cancer cells or by synthesis of m-RNA for HGF and may affect patient prognosis, 7,10) serum or plasma HGF content has not been regarded as a prognostic factor. Indeed, tumor HGF content or production and its autocrine- 16) or paracrine-like effects 7) may be strong prognostic factors, but do not explain clinical findings in patients showing tumor relapses after surgery with rapid growth detected in annual radiological examinations.…”

Section: Survival Analysismentioning

confidence: 99%

“…It has also been reported that tumor HGF content has prognostic implications in patients with non-small cell lung carcinoma. [1][2][3][4][5][6] Open thoracotomy and pulmonary resection are invasive procedures used for treating lung cancer. Major surgical operations inevitably stimulate the blood clotting system.…”

Section: Introductionmentioning

confidence: 99%

Plasma Hepatocyte Growth Factor Elevation May Be Associated with Early Metastatic Disease in Primary Lung Cancer Patients

Hosoda

Hayashi

Tukada

et al. 2012

Ann Thorac Cardiovasc Surg

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Purpose: Hepatocyte growth factor (HGF), a ligand of the c-met proto-oncogene, exhibits activating effects on human lung cancer both in vitro and in vivo. However, few studies have reported the correlations between concentration changes of blood HGF and postsurgical prognosis. Methods: We evaluated whether surgery-related blood HGF elevation has prognostic significance in patients with surgically resected non-small cell lung cancer. We examined blood HGF concentration, c-met expression, and postoperative prognosis of 25 cases of primary resected, non-small cell lung cancer. Results: We divided the patients into 2 groups according to receiver operating characteristics curve analysis using 7.2 ng/mL as the cut-off value of blood HGF concentration. Survival curve analysis revealed that patients with a high level of HGF (over the cutoff value) exhibited a poor prognosis of metastatic disease, compared to those in the low-level group after curative surgery (log rank test, P = 0.020; Wilcoxon test, P = 0.016). Conclusion: Elevation of HGF in plasma may be an important prognostic factor for early metastatic disease in patients with primary lung cancer. Moreover, inhibition of HGF elevation may have therapeutic effects on early distant metastasis of lung cancer.

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Hepatocyte growth factor is predominantly expressed by the carcinoma cells in non–small-cell lung cancer

Cited by 42 publications

References 33 publications

MicroRNA-519c Suppresses Hypoxia-Inducible Factor-1α Expression and Tumor Angiogenesis

MicroRNA-519c Suppresses Hypoxia-Inducible Factor-1α Expression and Tumor Angiogenesis

Inhibition of the Met Receptor in Mesothelioma

Plasma Hepatocyte Growth Factor Elevation May Be Associated with Early Metastatic Disease in Primary Lung Cancer Patients

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