Hypoxia-induced autophagy contributes to radioresistance via c-Jun-mediated Beclin1 expression in lung cancer cells.

Reduced radiosensitivity of lung cancer cells represents a pivotal obstacle in clinical oncology. The hypoxia-inducible factor (HIF)-1α plays a crucial role in radiosensitivity, but the detailed mechanisms remain elusive. A relationship has been suggested to exist between hypoxia and autophagy recently. In the current study, we studied the effect of hypoxia-induced autophagy on radioresistance in lung cancer cell lines. A549 and H1299 cells were cultured under normoxia or hypoxia, followed by irradiation at dosage ranging from 0 to 8 Gy. Clonogenic assay was performed to calculate surviving fraction. EGFP-LC3 plasmid was stably transfected into cells to monitor autophagic processes. Western blotting was used to evaluate the protein expression levels of HIF-1α, c-Jun, phosphorylated c-Jun, Beclin 1, LC3 and p62. The mRNA levels of Beclin 1 were detected by qRT-PCR. We found that under hypoxia, both A549 and H1299 cells were radio-resistant compared with normoxia. Hypoxia-induced elevated HIF-1α protein expression preferentially triggered autophagy, accompanied by LC3 induction, EGFP-LC3 puncta and p62 degradation. In the meantime, HIF-1α increased downstream c-Jun phosphorylation, which in turn upregulated Beclin 1 mRNA and protein expression. The upregulation of Beclin 1 expression, instead of HIF-1α, could be blocked by SP600125 (a specific inhibitor of c-Jun NH2-terminal kinase), followed by suppression of autophagy. Under hypoxia, combined treatment of irradiation and chloroquine (a potent autophagy inhibitor) significantly decreased the survival potential of lung cancer cells in vitro and in vivo. In conclusion, hypoxia-induced autophagy through evaluating Beclin1 expression may be considered as a target to reverse the radioresistance in cancer cells.

Nab-paclitaxel plus S-1 versus oxaliplatin plus S-1 as first-line treatment in advanced gastric cancer: results of a multicenter, randomized, phase III trial (GAPSO study).

Background: This study aimed to investigate the superiority of nab-paclitaxel plus S-1 (AS) over oxaliplatin plus S-1 (SOX) in patients with advanced gastric cancer (AGC). Methods: In this multicenter, randomized, phase III superiority trial, eligible patients with unresectable, locally advanced gastric adenocarcinoma were recruited and randomly assigned (1:1) to receive AS (nab-paclitaxel 260 mg/m2 on day 1 or 130 mg/m2 on days 1 and 8; oral S-1 40-60 mg twice daily for 14 days) or SOX (130 mg/m2 oxaliplatin on day 1; oral S-1 40-60 mg twice daily for 14 days) every 3 weeks for up to six cycles. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival, objective response rate, and safety. Results: Owing to slow enrolment, an unplanned interim analysis was performed, resulting in the early termination of the study on 31 December 2021 (data cutoff). Between March 2019 and March 2021, 97 patients (AS, n = 48; SOX, n = 49) were treated and evaluated for efficacy and safety of AS and SOX. As of the data cutoff, the median follow-up was 23.13 months [95% confidence interval (CI), 13.39-32.87]. The median PFS was 9.03 months (95% CI, 6.50-11.56) in the AS group and 5.07 months (95% CI, 4.33-5.81) in the SOX group, demonstrating a better PFS tendency following AS treatment than SOX treatment (hazard ratio = 0.59; 95% CI, 0.37-0.94; p = 0.03). The most common grade 3 or worse adverse events were anemia, neutropenia, and leukopenia in both groups, with a higher incidence of thrombocytopenia in the SOX group. Conclusion: Although this study was terminated early, the results demonstrated a better PFS tendency in patients with AGC who were treated with AS than in those treated with SOX, with controllable toxicities. Trial registration: Clinical Trials.gov identifiers: NCT03801668. Registered January 11, 2019.

Identification of BTG1 Status in Solid Cancer for Future Researches Using a System Review and Meta-analysis.

Abundant studies have been conducted to identify how B-cell translocation gene 1 protein (BTG1) gene affects the differentiation, proliferation, metastasis of cancer cells, and how it further regulates the generation or development of diseases to influence the prognosis of patients. However, the data from single research were not powerful enough. The correlations between BTG1 expression and mechanisms of tumorigenesis or prognosis of patients are still in controversial. Our system review and meta-analysis provided a complete explanation about the association between BTG1 expression and clinicopathological features or prognosis of patients, which further laid a foundation for future research on BTG1. Fifteen eligible studies consisting of 1992 participants were included. We uncovered that BTG1 expression in solid tumors was associated with lymph node status (RR=0.66, 95% CI: 0.58-0.75, P=0.142), TMN stage status (RR=2.13, 95% CI: 1.71-2.65, P=0.001), T category (RR=1.90, 95% CI: 1.20-3.00, P=0.000), histological differentiation (RR=1.91, 95% CI: 1.55-2.37, P=0.012), vascular invasion (RR=0.90, 95% CI: 0.57-1.41, P=0.001). BTG1 low expression was significantly associated with overall survival (OS) (HR=0.47, 95% CI: 0.38-0.67, P=0.000). It concluded that BTG1 possessed the potential value for future research and could be recommended as a significant biomarker in solid tumor.

Influence of position and radiation technique on organs at risk in radiotherapy of rectal cancer.

The influence of the position and radiation technique on the organs at risk (OARs) in radiotherapy of rectal cancer was evaluated. The relationship between the volume of irradiated small bowel (VSB) and acute bowel toxicity was determined. A total of 97 cases of rectal cancer were retrospectively randomized to receive radiotherapy with the designated treatment positions and radiation plans. Among 64 patients in the supine position, 32 patients were given three-dimensional conformal radiotherapy (3DCR) and 32 patients were subjected to intensity-modulated radiation therapy (IMRT) respectively. The rest 33 patients were treated with 3DCRT in the prone position with a belly board. The VSB was calculated for doses from 5 to 45 Gy at an interval of 5 Gy. With prescription dose in planned target volume (PTV) of 50 Gy, the dose distribution, conformal index for PTV (CIPTV), dose-volume histogram (DVH) of OARs, the correlation of VSB and the acute toxicity were compared. The results were shown as follows: (1) Among the 3 methods, there were no differences in PTV's converge including V95 and D95; (2) For IMRT under a supine position, CIPTV was closest to 1, the mean dose of small bowel decreased (P<0.05), and the mean VSB from V30 to V45 significantly decreased (P<0.05). (3) For 3DCRT with a belly board under a prone position, the mean dose and the mean VSB from 40 to 45 Gy were less than those for 3DCRT under a supine position (P<0.05); (4) Mean proportion of VSB was significantly greater in the patients experiencing diarrhea grade 2-4 than in those with diarrhea grade 0-1 at dose levels from V30 to V45 (P<0.05). It was concluded that for the radiotherapy of rectal cancer, IMRT technique might decrease the high-dose VSB to reduce the risk of acute injury. 3DCRT with a belly board under a prone position is superior to 3DCRT under a supine position, which could be a second choice for radiation of rectal cancer.