The Roles of a Novel Lncrna Linat in Regulating Tgf-Beta Signaling Dynamics and Tumor Malignancies

Emerging studies reveal that long non-coding RNAs (lncRNAs) play crucial roles in many cellular pathways and processes, including tumor progression. Although a fast-growing list of lncRNAs has been identified to associate with tumorigenesis and progression, their underlying mechanisms in tumor progression remain largely elusive. In this proposal, we aim to decipher the function and underlying mechanism of a novel lncRNA, LINAT (Long Intergenic RNA Activated by TGF-beta) in tumor progression. Our preliminary data revealed that LINAT high expression correlates with poor survival and invasive phenotype in human breast and liver cancers (HCC). LINAT high expression also correlates with severe malignant caner subtype, such as TNBC (Triple Negative Breast Cancer), and higher pathological stage in HCC. Consistent with these clinical results, LINAT promotes multiple malignant traits of solid cancer, including migration, invasion, EMT and stemness. Mechanistically, LINAT positively regulates TGF-beta/Smad signaling, and interacts with both Smad3 and Smad4. Importantly, LINAT itself is induced by TGF-beta in a Smad3/4-dependent manner, suggests a role of LINAT in mediating a positive feedback regulation of TGF-beta/Smad signaling, leading to a prolonged signaling duration to favor a tumor-promoting outcome. This proposal includes four Specific Aims. Aim 1 will test the functions of LINAT in promoting TGF-beta/Smad signaling and tumor malignancies in HCC. This could extend our findings from breast cancer to HCC, thereby establishing a more generalized oncogenic role of LINAT. Aim 2 will dissect the molecular mechanism by which LINAT promotes TGF-beta/Smad signaling, including the enhancement of Smad3/4 complex formation and/or the loading of Smad3/4 complex onto the TGF-beta responsive promoters. The critical regions of LINAT that are responsible for its promotion of TGF-beta/Smad signaling will also be identified. Aim 3 will investigate the ability of LINAT to mediate a positive feedback regulation of TGF-beta/Smad signaling to favor a tumor-promoting outcome. Both individual gene-based and systematic approaches will be conducted. Aim 4 will investigate the roles of LINAT in cancer metastasis via two complementary animal models i.e., experimental metastasis and orthotopic models as well as in drug resistance via in vitro and in vivo models. Additionally, we will test the therapeutic value of LINAT targeting in anti-cancer therapy using cancer cell lines and patient-derived xenograft (PDX) models. The three-year project integrates both basic and translational aspects and will provide important insights into the function and mechanism of a novel lncRNA LINAT in cancer progression. Results derived from this study would potentially confer prognostic value and benefit future design of lncRNA-based therapeutic strategies for treating cancer.