CMTR1 promotes colorectal cancer cell growth and immune evasion by transcriptionally regulating STAT3.

CMTR1, also called IFN-stimulated gene 95 kDa protein (ISG95), is elevated by viral infection in a variety of cells. However, the functions of CMTR1 in colorectal cancer (CRC), especially its roles in tumorigenesis and immune regulation, remain unclear. Here, we first identified CMTR1 as a novel oncogene in colorectal cancer. Based on The Cancer Genome Atlas (TCGA) database exploration and human tissue microarray (TMA) analysis, we found that CMTR1 expression was markedly higher in CRC tissues than in adjacent normal tissues. High CMTR1 expression was correlated with poor prognosis in CRC patients. Knockdown (KD) of CMTR1 significantly suppressed cell proliferation and tumorigenicity both in vitro and in vivo, whereas overexpression of CMTR1 resulted in the opposite effects. KEGG pathway analysis revealed differential enrichment in the JAK/STAT signaling pathway in colorectal cancer cells with CMTR1 KD. Mechanistically, suppression of CMTR1 expression inhibited RNAPII recruitment to the transcription start site (TSS) of STAT3 and suppressed STAT3 expression and activation. Furthermore, the efficacy of PD1 blockade immunotherapy was prominently enhanced in the presence of CMTR1 KD via increased infiltration of CD8 + T cells into the tumor microenvironment. Overall, it appears that CMTR1 plays a key role in regulating tumor cell proliferation and antitumor immunity.

APP promotes osteoblast survival and bone formation by regulating mitochondrial function and preventing oxidative stress.

Amyloid precursor protein (APP) is ubiquitously expressed in various types of cells including bone cells. Mutations in App gene result in early-onset Alzheimer's disease (AD). However, little is known about its physiological function in bone homeostasis. Here, we provide evidence for APP's role in promoting bone formation. Mice that knocked out App gene (APP-/-) exhibit osteoporotic-like deficit, including reduced trabecular and cortical bone mass. Such a deficit is likely due in large to a decrease in osteoblast (OB)-mediated bone formation, as little change in bone resorption was detected in the mutant mice. Further mechanical studies of APP-/- OBs showed an impairment in mitochondrial function, accompanied with increased reactive oxygen species (ROS) and apoptosis. Intriguingly, these deficits, resemble to those in Tg2576 animal model of AD that expresses Swedish mutant APP (APPswe), were diminished by treatment with an anti-oxidant NAC (n-acetyl-l-cysteine), uncovering ROS as a critical underlying mechanism. Taken together, these results identify an unrecognized physiological function of APP in promoting OB survival and bone formation, implicate APPswe acting as a dominant negative factor, and reveal a potential clinical value of NAC in treatment of AD-associated osteoporotic deficits.

Swedish mutant APP suppresses osteoblast differentiation and causes osteoporotic deficit, which are ameliorated by N-acetyl-L-cysteine.

Reduced bone mineral density and hip fracture are frequently observed in patients with Alzheimer's disease (AD). However, mechanisms underlying their association remain poorly understood. Amyloid precursor protein (APP) is a transmembrane protein that is ubiquitously expressed in bone marrow stromal cells (BMSCs), osteoblasts (OBs), macrophages (BMMs), and osteoclasts (OCs). Mutations in the APP gene identified in early-onset AD patients are believed to cause AD. But little is known about APP's role in bone remodeling. Here, we present evidence for Swedish mutant APP (APPswe) in suppression of OB differentiation and function in culture and in mouse. APP expression in BMSCs increases during aging. Ubiquitous expression of APPswe in young adult Tg2576 transgenic mice (under the control of a prion promoter) recaptured skeletal "aging-like" deficits, including decreased OB genesis and bone formation, increased adipogenesis and bone marrow fat, and enhanced OC genesis and bone resorption. Remarkably, selective expression of APPswe in mature OB-lineage cells in TgAPPswe-Ocn mice (under the control of osteocalcin [Ocn] promoter-driven Cre) also decreased OB genesis and increased OC formation, resulting in a trabecular bone loss. These results thus suggest a cell-autonomous role for APPswe in suppressing OB formation and function, but a nonautonomous effect on OC genesis. Notably, increased adipogenesis and elevated bone marrow fat were detected in young adult Tg2576 mice, but not in TgAPPswe-Ocn mice, implying that APPswe in BMSCs and/or multicell types in bone marrow promotes bone marrow adipogenesis. Intriguingly, the skeletal aging-like deficits in young adult Tg2576 mice were prevented by treatment with N-acetyl-L-cysteine (NAC), an antioxidant, suggesting that reactive oxygen species (ROS) may underlie APPswe-induced osteoporotic deficits. Taken together, these results demonstrate a role for APPswe in suppressing OB differentiation and bone formation, implicate APPswe as a detrimental factor for AD-associated osteoporotic deficit, and reveal a potential clinical value of NAC in the treatment of osteoporotic deficits. © 2013 American Society for Bone and Mineral Research.