ABSTRACT
The abnormality of surfactant protein C (SFTPC) has been linked to the development of a number of interstitial lung diseases, according to mounting evidence. Nonetheless, the function and mechanism of SFTPC in the biological progression of lung adenocarcinoma (LUAD) remain unclear. Analysis of public datasets and testing of clinical samples suggested that SFTPC expression was abnormally low in LUAD, which was associated with the onset and poor prognosis of LUAD. The SFTPC-related risk score was derived using least absolute shrinkage and selection operator Cox regression as well as multivariate Cox regression. The risk score was highly correlated with tumor purity and tumor mutation burden, and it could serve as an independent prognostic indicator for LUAD. Low-risk LUAD patients may benefit more from CTLA-4 or/and PD-1 inhibitors. Overall, the risk score is useful for LUAD patient prognostication and treatment guidance. Moreover, in vitro and in vivo experiments demonstrated that SFTPC inhibits the proliferation of LUAD by inhibiting PI3K/AKT/mTOR signaling transduction. These results reveal the molecular mechanism by which SFTPC inhibits the proliferation of LUAD and suggest that SFTPC could be a new therapeutic target for LUAD.
Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Humans , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Lung Neoplasms/pathology , Cell Proliferation/genetics , Adenocarcinoma of Lung/metabolism , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Gene Expression Regulation, Neoplastic , Pulmonary Surfactant-Associated Protein C/genetics , Pulmonary Surfactant-Associated Protein C/metabolismABSTRACT
The proportions of the various muscle fiber types are important in the regulation of skeletal muscle metabolism, as well as animal meat production. Four-and-a-half LIM domain protein 3 (FHL3) is highly expressed in fast glycolytic muscle fibers and differentially regulates the expression of myosin heavy chain (MyHC) isoforms at the cellular level. Whether FHL3 regulates the transformation of muscle fiber types in vivo and the regulatory mechanism is unclear. In this study, muscle-specific FHL3 transgenic mice were generated by random integration, and lentivirus-mediated gene knockdown or overexpression in muscles of mice or pigs was conducted. Functional analysis showed that overexpression of FHL3 in muscles significantly increased the proportion of fast-twitch myofibers and muscle mass but decreased muscle succinate dehydrogenase (SDH) activity and whole-body oxygen consumption. Lentivirus-mediated FHL3 knockdown in muscles significantly decreased muscle mass and the proportion of fast-twitch myofibers. Mechanistically, FHL3 directly interacted with the Yin yang 1 (YY1) DNA-binding domain, repressed the binding of YY1 to the fast glycolytic MyHC2b gene regulatory region, and thereby promoted MyHC2b expression. FHL3 also competed with EZH2 to bind the repression domain of YY1 and reduced H3K27me3 enrichment in the MyHC2b regulatory region. Moreover, FHL3 overexpression reduced glucose tolerance by affecting muscle glycolytic metabolism, and its mRNA expression in muscle was positively associated with hemoglobin A1c (HbA1c) in patients with type 2 diabetes. Therefore, FHL3 is a novel potential target gene for the treatment of muscle metabolism-related diseases and improvement of animal meat production.
