| 1. |
- Hu, Wenjun, et al.
(författare)
-
Heterogeneous nuclear ribonucleoprotein L facilitates recruitment of 53BP1 and BRCA1 at the DNA break sites induced by oxaliplatin in colorectal cancer
- 2019
-
Ingår i: Cell Death and Disease. - : NATURE PUBLISHING GROUP. - 2041-4889. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- Although oxaliplatin is an effective chemotherapeutic drug for treatment of colorectal cancer (CRC), tumor cells can develop mechanisms to evade oxaliplatin-induced cell death and show high tolerance and acquired resistance to this drug. Heterogeneous nuclear ribonucleoprotein L (hnRNP L) has been proved to play a critical role in DNA repair during IgH class switch recombination (CSR) in B lymphocytes, while, its role in CRC and chemotherapeutic resistance remain unknown. Our study aims to uncover an unidentified mechanism of regulating DNA double-strand breaks (DSBs) by hnRNP L in CRC cells treated by oxaliplatin. In present study, we observed that knockdown of hnRNP L enhanced the level of DNA breakage and sensitivity of CRC cells to oxaliplatin. The expression of key DNA repair factors (BRCA1, 53BP1, and ATM) was unaffected by hnRNP L knockdown, thereby excluding the likelihood of hnRNP L mediation via mRNA regulation. Moreover, we observed that phosphorylation level of ATM changed oppositely to 53BP1 and BRCA1 in the CRC cells (SW620 and HCT116) which exhibit synergistic effect by oxaliplatin plus hnRNP L impairment. And similar phenomenon was observed in the foci formation of these critical repair factors. We also found that hnRNP L binds directly with these DNA repair factors through its RNA-recognition motifs (RRMs). Analysis of cell death indicated that the RRMs of hnRNP L are required for cell survival under incubation with oxaliplatin. In conclusion, hnRNP L is critical for the recruitment of the DNA repair factors in oxaliplatin-induced DSBs. Targeting hnRNP L is a promising new clinical approach that could enhance the effectiveness of current chemotherapeutic treatment in patients with resistance to oxaliplatin.
|
|
| 2. |
- Luo, Bin, et al.
(författare)
-
Preoperative Radiotherapy Decision-Tree for Rectal Cancer Patients: A Real-World Analysis Based on the Swedish Colorectal Cancer Registry
- 2023
-
Ingår i: Clinical colorectal cancer. - : CIG MEDIA GROUP, LP. - 1533-0028. ; 22:3, s. 280-290
-
Tidskriftsartikel (refereegranskat)abstract
- There are 3 widely used preoperative radiotherapy (RT) procedures in rectal cancer treatment including long course RT (LRT), short-course RT with delayed surgery (SRTW), and short-course RT with immediate surgery (SRT), without solid evidence to clarify which is best in terms of patient survival. We assessed 7766 rectal cancer patients from the Swedish Registry with adjusted confounding factors, showing that single RT procedure was suitable for all the patients. These RT procedures showed different effects on survival of the patients with various age and clinical stage, and therefore the more tailored RT strategy for rectal cancer patients should based on these predictive factors. Background: There are 3 widely used preoperative radiotherapy (RT) procedures in rectal cancer treatment including long-course RT (LRT), short-course RT with delayed surgery (SRTW), and short-course RT with immediate surgery (SRT). However, further evidence is required to determine which treatment option results in more optimal patient survival. Methods: This Swedish Colorectal Cancer Registry-based retrospective study of real-world data included 7766 stage I-III rectal cancer patients, of which 2982, 1089, 763, and 2932 patients received no RT (NRT), LRT, SRTW, and SRT, respectively. The Kaplan-Meier sur vival cur ve and Cox proportional hazard multivariate model were used to identify potential risk factors and to examine the independent association of RT with patient survival after adjusting for baseline confounding factors. Results: RT effects on survival differed by age and clinical T stage (cT) subgroups. Subsequent survival analysis by age and cT subgroups confirmed that patients >70 years old with cT4 benefited from any RT ( P < .001, NRT as reference) and equally from any RT ( P > .05 pairwise between RTs). In contrast, for cT3 patients =70 years, SRT and LRT were associated with better survival than SRTW ( P < .001). In patients < 70 years, LRT and SRTW had superior survival benefits in cT4 patients but inferior to SRT ( P < .001); SRT was the only effective treatment in the cT3N+ subgroup ( P = .032); patients with cT3N0 and < 70 years did not benefit from any RT. Conclusion: This study suggests that preoperative RT strategies may have varying effects on the survival of rectal cancer patients, depending on their age and clinical stage.
|
|
| 3. |
- Xie, Xuqin, et al.
(författare)
-
APR-246 Enhances Colorectal Cancer Sensitivity to Radiotherapy
- 2023
-
Ingår i: Molecular Cancer Therapeutics. - : AMER ASSOC CANCER RESEARCH. - 1535-7163 .- 1538-8514. ; 22:8, s. 947-961
-
Tidskriftsartikel (refereegranskat)abstract
- p53 mutation is common and highly related to radiotherapy resistance in rectal cancer. APR-246, asa small molecule, can restore the tumor-suppressor function to mutant p53. As there is currently no existing study on combining APR-246 with radiation in rectal cancer, our objective was to investigate whether APR-246 could enhance the sensitivity of colorectal cancer cells, regardless of their p53 status, to radiation treatment. The combination treatment had synergistic effects on HCT116p53-R248W/- (p53Mut) cells, followed by HCT116p53+/+ [wild-type p53 (p53WT)] cells, and exhibited an additive effect on HCT116p53-/- (p53Null) cells through inhibiting proliferation, enhancing reactive oxygen species, and apoptosis. The results were confirmed in zebrafish xenografts. Mechanistically, p53Mut and p53WT cells shared more activated pathways and differentially expressed genes following the combination treat-ment, compared with p53Null cells, although the combination treatment regulated individual pathways in the different cell lines. APR-246 mediated radiosensitization effects through p53-dependent and-independent ways. The results may provide evidence for a clinical trial of the combination in patients with rectal cancer.
|
|
