MicroRNA-135b promotes lung cancer metastasis by regulating multiple targets in the Hippo pathway and LZTS1

Abstract

Dysregulation of microRNAs has a critical role in cancer progression. Here we identify an intronic microRNA, miR-135b that is upregulated in highly invasive non-small-cell lung cancer cells. Expression of miR-135b enhances cancer cell invasive and migratory abilities in vitro and promotes cancer metastasis in vivo, while specific inhibition of miR-135b by a miR-135b-specific molecular sponge and antagomirs suppresses cancer cell invasion, orthotopic lung tumour growth and metastasis in a mouse model. miR-135b targets multiple key components in the Hippo pathway, including LATS2, b-TrCP and NDR2, as well as LZTS1. Expression of miR-135b, LZTS1, LATS2 and nuclear TAZ predicts poor outcomes of non-small-cell lung cancer. We find that miR-135b is dually regulated by DNA demethylation and nuclear factor-kappaB signalling, implying that abnormal expression of miR-135b in cancer may result from inflammatory and epigenetic modulations. We conclude that miR-135b is an oncogenic microRNA and a potential therapeutic target for non-small-cell lung cancer.

MicroRNA-135b promotes proliferation, invasion and migration of osteosarcoma cells by degrading myocardin

“…Overexpression of miR-135b conferred an increased tumorigenic ability to the relatively benign CL1-0 cells, resulting in >4-fold greater tumor burden in xenograft mouse models. In vivo, stable expression of a miR-135b antagonist decreased the number of metastatic tumor nodules in mice injected with highly invasive CL1-5-F4 cells shown to have high levels of miR-135b (15). Clinically, high levels of miR-135b in lung cancer specimens significantly correlated with decreased overall survival (15).…”

“…In vivo, stable expression of a miR-135b antagonist decreased the number of metastatic tumor nodules in mice injected with highly invasive CL1-5-F4 cells shown to have high levels of miR-135b (15). Clinically, high levels of miR-135b in lung cancer specimens significantly correlated with decreased overall survival (15). Although the expression of miR-135b is upregulated in osteosarcoma and miR-135b functions as an oncogene in other malignant tumors suggesting that it might be a target for malignant tumor therapy, its roles still keep emerging in osteosarcoma.…”

“…The expression of miR-135b is upregulated in osteosarcoma (8) and miR-135b functions as an oncogene in other malignant tumors suggesting that it might be a target for malignant tumor therapy (14)(15)(16)(17)(18), but its roles still keep emerging in osteosarcoma.…”

miR141–CXCL1–CXCR2 Signaling–Induced Treg Recruitment Regulates Metastases and Survival of Non–Small Cell Lung Cancer

“…Studies have shown that miRNAs are involved in cancer pathogenesis by regulating tumor growth and metastasis (30,31). Therefore, more and more researchers focus on their potential applications in cancer therapeutics (32,33).…”

MiRNA Molecular Profiles in Human Medical Conditions: Connecting Lung Cancer and Lung Development Phenomena

“…In accordance with two studies, upregulation of miR-137, miR-372, miR-182, miR-486, miR-30d, miR-1, miR-499, miR-221, and let-7a are correlated with disease-free survival in 122 NSCLC patients (Yu et al, 2008;Hu et al, 2010). are other examples of miRNAs with oncogenic properties in lung cancer (Liu et al, 2010;Li et al, 2012;Liu et al, 2012c;Lin et al, 2013). LATS2 and PPP2R2A are tumor suppressors which are repressed by miR-31 as it was shown by Liu et al representing that miR-31 is an oncomir.…”