• melanoma
• proteomics

• 32330062; 31972933 National Natural Science Foundation of China (National Science Foundation of China)
• 32201212 National Natural Science Foundation of China (National Science Foundation of China)
• 82101750 National Natural Science Foundation of China (National Science Foundation of China)
• 2023TQ0063; GZC20230524 China Postdoctoral Science Foundation
• National Key Research and Development Program of China (2022YFA1303200 [C.D.] and 2022YFA1303201 [C.D.]), Program of Shanghai Academic/ Technology Research Leader (22XD1420100 [C.D.]), the Major Project of Special Development Funds of Zhangjiang National Independent Innovation Demonstration Zone (ZJ2019-ZD-004 [C.D.]), the Science and Technology Commission of Shanghai Municipality (2017SHZDZX01 [C.D.]), the Fudan Original Research Personalized Support Project [C.D.]

• CircRNAs
• Colorectal cancer
• Glucose metabolism
• Warburg effect

• CYXZ2022-47 Lanzhou University Second Hospital
• 20220060024 Lanzhou University
• 82060800 National Natural Science Foundation of China
• 20JR10RA759 Gansu Province Youth Science and Technology Fund program
• GSWSKY2020-30 Science and Technology Program of Gansu Province

• dna
• human lung cancer
• pk

• Humans
• Small Cell Lung Carcinoma
• DNA-Activated Protein Kinase
• Prognosis
• Lung Neoplasms/genetics
• Carcinoma, Non-Small-Cell Lung/genetics
• Adenocarcinoma/genetics
• Carcinoma, Squamous Cell/genetics
• DNA

• Alternative end-joining pathways
• Double-strand break
• Double-strand break repair
• Hematologic malignancies
• Non-homologous end-joining
• Targeted therapy

• Base excision repair
• DNA breaks
• DNA mismatch repair
• DNA repair
• Hematologic neoplasms
• Homologous recombination
• Non-Homologous End joining
• Nucleotide excision repair

The changes in dietary patterns cause an increased incidence of colorectal cancer (CRC) globally. We aimed to explore the mechanism behind circular RNA circ_0136666 in the progression of CRC.

The expression of circ_0136666, miR-383 and cAMP response element binding protein 1 (CREB1) was detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell proliferation, apoptosis and glycolysis were measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry and glucose or lactate detection kit, respectively. The combination between miR-383 and circ_0136666 or CREB1 in 293T cells was predicted by Circular RNA Interactome or Starbase software and confirmed by dual-luciferase reporter assay. Western blot assay was performed to detect the abundance of CREB1, hexokinase 2 (HK2) and lactate dehydrogenase A (LDHA) in CRC cells. Murine xenograft model was established to verify the function of circ_0136666 in vivo.

circ_0136666 was aberrantly up-regulated in CRC tissues and cells, and it promoted the proliferation and glycolysis and inhibited the apoptosis of CRC cells. circ_0136666 accelerated the progression of CRC through directly targeting and down-regulating miR-383. CREB1 could bind to miR-383 in 293T cells. The overexpression of CREB1 reversed the inhibitory effects of miR-383 accumulation on the proliferation and glycolysis and the promoting impact on the apoptosis of CRC cells. The enrichment of CREB1 was modulated by circ_0136666/miR-383 signaling in CRC cells. The glycolysis-related proteins (HK2 and LDHA) were modulated by circ_0136666/miR-383/CREB1 axis in CRC cells. circ_0136666 accelerated the growth of CRC tumors via circ_0136666/miR-383/CREB1 axis in vivo.

circ_0136666 deteriorated CRC through miR-383/CREB1 axis. circ_0136666/miR-383/CREB1 axis might be an underlying therapeutic target for CRC therapy.

• CREB1
• apoptosis
• circ_0136666
• colorectal cancer
• glycolysis
• miR-383
• proliferation

• Cancer
• Clinical trials
• DNA-PK
• Non-homologous end-joining
• Targeting

• PRKDC
• breast cancer
• cell cycle
• cell proliferation
• p38 MAPK

• Chemoresistance
• DNA damage repair
• Gastric cancer
• PRKDC

• Apoptosis
• DNA Damage/genetics
• DNA-Activated Protein Kinase/genetics
• DNA-Binding Proteins/metabolism
• Humans
• Prognosis
• Stomach Neoplasms/diagnosis
• Stomach Neoplasms/genetics
• Stomach Neoplasms/pathology

• DNA-dependent protein kinase catalytic subunit
• laryngeal neoplasm
• squamous cell carcinoma

• Biomarker
• PRKDC
• Prognosis
• Prostate cancer
• Tumor progression

Due to a wide range of clinical response in patients undergoing neo-adjuvant chemoradiation for rectal cancer it is essential to understand molecular factors that lead to the broad response observed in patients receiving the same form of treatment. Despite extensive research in this field, the exact mechanisms still remain elusive. Data raging from DNA-repair to specific molecules leading to cell survival as well as resistance to apoptosis have been investigated. Individually, or in combination, there is no single pathway that has become clinically applicable to date. In the following review, we describe the current status of various pathways that might lead to resistance to the therapeutic applications of ionizing radiation in rectal cancer.

• Ionizing radiation
• DNA double-strand break
• Non-homologous end-joining pathway
• DNA-PKcs
• Ku proteins
• Complete pathological response
• Radiation therapy
• Apoptosis
• Angiogenesis

Waldenström's macroglobulinemia (WM) is a clonal B-cell lymphoproliferative disorder (LPD) of post-germinal center nature. Despite the fact that the precise molecular pathway(s) leading to WM remain(s) to be elucidated, a hallmark of the disease is the absence of the immunoglobulin heavy chain class switch recombination. Using two-dimensional gel electrophoresis, we compared proteomic profiles of WM cells with that of other LPDs. We were able to demonstrate that WM constitutes a unique proteomic entity as compared with chronic lymphocytic leukemia and marginal zone lymphoma. Statistical comparisons of protein expression levels revealed that a few proteins are distinctly expressed in WM in comparison with other LPDs. In particular we observed a major downregulation of the double strand repair protein Ku70 (XRCC6); confirmed at both the protein and RNA levels in an independent cohort of patients. Hence, we define a distinctive proteomic profile for WM where the downregulation of Ku70—a component of the non homologous end-joining pathway—might be relevant in disease pathophysiology.

• Acid Anhydride Hydrolases
• Antigens, Nuclear/biosynthesis
• Antigens, Nuclear/genetics
• DNA Repair
• DNA Repair Enzymes/biosynthesis
• DNA Repair Enzymes/genetics
• DNA, Neoplasm/genetics
• DNA-Binding Proteins/biosynthesis
• DNA-Binding Proteins/genetics
• Gene Expression Profiling/methods
• Genetic Predisposition to Disease
• Humans
• Ku Autoantigen
• Lymphoma, Non-Hodgkin/genetics
• Lymphoma, Non-Hodgkin/metabolism
• MRE11 Homologue Protein
• Multiple Myeloma/genetics
• Multiple Myeloma/metabolism
• Neoplasm Proteins/biosynthesis
• Neoplasm Proteins/genetics
• Reverse Transcriptase Polymerase Chain Reaction/methods

C-Myc is a short-lived oncoprotein that is destroyed by ubiquitin-mediated proteolysis. Dysregulated accumulation of c-Myc commonly occurs in human cancers. Some of those cases with the dysregulated c-Myc protein accumulation are attributed to gene amplification or increased mRNA expression. However, the abnormal accumulation of c-Myc protein is also a common finding in human cancers with normal copy number and transcription level of c-Myc gene. It seems that the mechanistic dysregulation in the control of c-Myc protein stabilization is another important hallmark associated with c-Myc accumulation in cancer cells. Here we report a novel mechanistic pathway through which DNA-dependent protein kinase catalytic subunit (DNA-PKcs) modulates the stability of c-Myc protein.

Firstly, siRNA-mediated silencing of DNA-PKcs strikingly downregulated c-Myc protein levels in HeLa and HepG2 cells, and simultaneously decreased cell proliferation. The c-Myc protein level in DNA-PKcs deficient human glioma M059J cells was also found much lower than that in DNA-PKcs efficient M059K cells. ATM deficiency does not affect c-Myc expression level. Silencing of DNA-PKcs in HeLa cells resulted in a decreased stability of c-Myc protein, which was associated the increasing of c-Myc phosphorylation on Thr58/Ser62 and ubiquitination level. Phosphorylation of Akt on Ser473, a substrate of DNA-PKcs was found decreased in DNA-PKcs deficient cells. As the consequence, the phosphorylation of GSK3 β on Ser9, a negatively regulated target of Akt, was also decreased, and which led to activation of GSK 3β and in turn phosphorylation of c-Myc on Thr58. Moreover, inhibition of GSK3 activity by LiCl or specific siRNA molecules rescued the downregulation of c-Myc mediated by silencing DNA-PKcs. Consistent with this depressed DNA-PKcs cell model, overexpressing DNA-PKcs in normal human liver L02 cells, by sub-chronically exposing to very low dose of carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), increased c-Myc protein level, the phosphorylation of Akt and GSK3 β, as well as cell proliferation. siRNA-mediated silencing of DNA-PKcs in this cell model reversed above alterations to the original levels of L02 cells.

A suitable DNA-PKcs level in cells is necessary for maintaining genomic stability, while abnormal overexpression of DNA-PKcs may contribute to cell proliferation and even oncogenic transformation by stabilizing the c-Myc oncoprotein via at least the Akt/GSK3 pathway. Our results suggest DNA-PKcs a novel biological role beyond its DNA repair function.

AIM: To characterize the difference in DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression between hepatocarcinoma tissues and non-tumor liver tissues, and to understand the biological significance of the altered expression of DNA-PKcs in cancer cells.

METHODS: DNA-PKcs expression was examined in 86 specimens of hepatocarcinoma and hepatic cholangiocarcinoma by immunohistochemistry analysis on tissue-arrays and ordinary pathological tissue slices. DNA-PKcs protein was detected in culture cells by Western blotting analysis. The siRNA was used to silence DNA-PKcs expression in HepG2 cells. Cell proliferation was evaluated by growth curve analysis, and radiosensitivity was tested using a colony-forming ability assay.

RESULTS: Tissue-array analysis showed that the proportions of cases with a DNA-PKcs expression level of < 25% (very low), 25%-50% (low), 51%-75% (medium) and > 75% (high) were 15%, 20%, 23.3% and 41.7%, respectively, among the 60 hepatocarcinoma tissue specimens. The proportions of the 64 normal liver tissues showing these DNA-PKcs expression levels were 68.7%, 10.9%, 12.6% and 7.8%, respectively. This result indicated that DNA-PKcs expression in cancer tissues was significantly higher than that in normal tissues (P = 0.0008). Immunohistochemistry analysis of ordinary pathological tissue slices also showed that DNA-PKcs levels in the hepatocarcinoma and hepatic cholangiocarcinoma tissues (total 26 specimens) were higher than those in the non-tumor liver tissues (P = 0.001). Moreover, the cultured human liver cancer cell lines HepG2, 7721 and 7402 also exhibited much higher levels of DNA-PKcs than normal liver LO2 cells. Silencing of DNA-PKcs mediated by siRNA resulted in not only an increased sensitivity of HepG2 cells to ionizing radiation, but also decreased proliferation HepG2 cells. We further demonstrated that the expression of c-Myc oncoprotein was also depressed following the down-regulation of DNA-PKcs.

CONCLUSION: DNA-PKcs is overexpressed in hepatocarcinoma tissues as well as cultured liver cancer cells. Targeting DNA-PKcs is an anticancer strategy acting through at least two mechanisms: directly decreasing the proliferation of cancer cells via, at least, depressing c-Myc oncoprotein; and sensitizing cancer cells to radiotherapy or chemotherapy with DNA-damaging agents.

• Hepatocarcinoma
• DNA-PKcs
• c-Myc
• Tissue array
• Small interfering RNA
• Cell proliferation
• Radiosensitization

• Aging/genetics
• Humans
• Neoplasms/chemistry
• Neoplasms/genetics
• Neoplasms/metabolism
• Telomere/chemistry
• Telomere/genetics
• Telomere/metabolism