Aptamers have the potential to be used as targeting ligands for cancer treatment as they form unique spatial structures. Methods: In this study, a DNA aptamer (T1) that accumulates in the tumor microenvironment was identified through in vivo selection and validation in breast cancer models. The use of T1 as a targeting ligand was evaluated by conjugating the aptamer to liposomal doxorubicin. Results: T1 exhibited a high affinity for both tumor cells and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Treatment with T1 targeted doxorubicin liposomes triggered apoptosis of breast cancer cells and PMN-MDSCs. Suppression of PMN-MDSCs, which serve an immunosuppressive function, leads to increased intratumoral infiltration of cytotoxic T cells. Conclusion: The cytotoxic and immunomodulatory effects of T1-liposomes resulted in superior therapeutic efficacy compared to treatment with untargeted liposomes, highlighting the promise of T1 as a targeting ligand in cancer therapy.

Rationale: Radioresistance is considered the main cause of local relapse in lung cancer. However, the molecular mechanisms of radioresistance remain poorly understood. This study investigates the role of CDK16 in radioresistance of human lung cancer cells. Methods: The expression levels of CDK16 were determined by immunohistochemistry in lung cancer tissues and adjacent normal lung tissues. Immunoprecipitation assay and GST pulldown were utilized to detect the protein-protein interaction. The phosphorylation of p53 was evaluated by in vitro kinase assay. Poly-ubiquitination of p53 was examined by in vivo ubiquitination assay. Cell growth and apoptosis, ROS levels and DNA damage response were measured for functional analyses. Results: We showed that CDK16 is frequently overexpressed in lung cancer cells and tissues, and high levels of CDK16 are correlated with lymph node stage and poor prognosis in lung cancer patients. Furthermore, we provided evidence that CDK16 binds to and phosphorylates p53 at Ser315 site to inhibit transcriptional activity of p53. Moreover, we uncovered that this phosphorylation modification accelerates p53 degradation via the ubiquitin/proteasome pathway. Importantly, we demonstrated that CDK16 promotes radioresistance by suppressing apoptosis and ROS production as well as inhibiting DNA damage response in lung cancer cells in a p53-dependent manner. Conclusion: Our findings suggest that CDK16 negatively modulates p53 signaling pathway to promote radioresistance, and therefore represents a promising therapeutic target for lung cancer radiotherapy.

Rationale: The molecular mechanisms underlying the pathogenesis of systemic insulin resistance in type 2 diabetes remain elusive. Growth hormone receptor (GHR) deficiency has long been known to improved insulin sensitivity. However, whether hepatic GHR overexpression or activation is a cause of insulin resistance is still unknown. The aim of this study was to identify the new role of GHR in systemic insulin resistance and explore the underlying mechanism. Method: Different samples obtained from obese humans, ob/ob mice, db/db mice, high-fat diet (HFD)-fed mice and primary mouse hepatocytes were used to evaluate the correlations between GHR and metabolic disorders. Recombinant adeno-associated viruses encoding GHR and STAT5 and GHR knockout mice were used to investigate the roles of hepatic GHR in glucose homeostasis. Tissue H&E, Oil Red O and PAS staining were performed for histomorphological analysis. Gel filtration chromatography was employed for the separation of serum RBP4-TTR complexes. Plasmids (related to GHR, STAT5 and HIF1α), siRNA oligos (siGHR and siSTAT5), luciferase activity and ChIP assays were used to explore the potential mechanism of hepatic GHR. Results: Here, we found that hepatic GHR expression was elevated during metabolic disorder. Accordingly, hepatic GHR overexpression disrupted systemic glucose homeostasis by promoting gluconeogenesis and disturbing insulin responsiveness in the liver. Meanwhile, hepatic GHR overexpression promoted lipolysis in white adipose tissue and repressed glucose utilization in skeletal muscle by promoting the circulating level of RBP4, which contributed to impaired systemic insulin action. A mechanistic study revealed that hepatic GHR disrupted systemic insulin sensitivity by increasing RBP4 transcription by activating STAT5. Additionally, overexpression of hepatic GHR promoted TTR transcriptional levels by enhancing the expression of HIF1α, which not only increased the protein stability of RBP4 but also inhibited renal clearance of RBP4 in serum. Conclusions: Hepatic GHR overexpression and activation accelerated systemic insulin resistance by increasing hepatic RBP4 production and maintaining circulating RBP4 homeostasis. Our current study provides novel insights into the pathogenesis of type 2 diabetes and its associated metabolic complications.