Hepatitis B virus X protein-induced SH2 domain-containing 5 (SH2D5) expression promotes hepatoma cell growth via an SH2D5-transketolase interaction.

Hepatitis B virus X protein (HBx) critically contributes to the development of hepatocellular carcinoma (HCC). However, the mechanisms by which HBx promotes HCC remain unclear. In the present study, using a combination of gene expression profiling and immunohistochemistry, we found higher levels of SH2 domain-containing 5 (SH2D5) in liver tissue from HBV-associated HCC (HBV-HCC) patients than in adjacent nontumor tissues. Moreover, HBV infection elevated SH2D5 levels, and we observed that HBx plays an important role in SH2D5 induction. We also found that HBx triggers SH2D5 expression through the NF-κB and c-Jun kinase pathways. Employing SH2D5 overexpression or knockdown, we further demonstrate that SH2D5 promotes HCC cell proliferation both in vitro and in vivo While investigating the mechanism of SH2D5-mediated stimulation of HCC cell proliferation, we noted that HBV induces SH2D5 binding to transketolase (TKT), a pentose phosphate pathway enzyme, thereby promoting an interaction between and signal transducer and activator of transcription 3 (STAT3). Furthermore, HBx stimulated STAT3 phosphorylation at Tyr-705 and promoted the activity and downstream signaling pathway of STAT3 via the SH2D5-TKT interaction. Taken together, our results suggest that SH2D5 is an HBV-induced protein capable of binding to TKT, leading to induction of HCC cell proliferation.

The safety and efficacy of immunotherapy and palliative radiotherapy in patients with metastatic non-small cell lung cancer: a systematic review and meta-analysis of 13 prospective studies.

OBJECTIVE: Whether palliative RT (pRT) can influence the prognosis of mNSCLC patients who are treated with immune checkpoint inhibitors (ICIs) is still under debate. Therefore, we performed a systematic review and meta-analysis to evaluate the efficacy and safety of pRT plus ICIs in mNSCLC patients. METHODS: PubMed, Cochrane, and Embase databases were searched, and only prospective studies and randomized controlled trials (RCTs) were included. All data were analyzed with Stata 14.0 and Review Manager Version 5.4 software. RESULTS: A total of 13 studies were included. The combined ORRs for the ICIs group, cRT plus ICIs group, and SBRT plus ICIs group were 0.22 (95% CI: 1.27, 4.04), 0.26 (95% CI: 0.04, 0.49), and 0.29 (95% CI: 0.17, 0.40), respectively. And PFS were 2.21 (95% CI: 1.71, 2.70), 4.63 (95% CI: 2.16, 7.09), and 7.38 (95% CI: 2.16, 12.60) months, respectively. OS was 5.96 (95% CI: 3.85, 8.07), 9.04 (95% CI: 6.49, 11.59), and 7.96 (95% CI: 4.02, 11.91) months for the above groups, respectively. For safety terms, patients receiving ICIs plus SBRT had an incidence of 5% (95% CI: 2%, 9%) for pneumonia. CONCLUSION: Patients with mNSCLC may benefit from the combination of ICIs and pRT therapy, but these findings need further validation.

Assessing the Relationship Between Liver Metastases and the Survival of Patients With Non-Small Cell Lung Cancer After Immune Checkpoint Inhibitors Treatment: A Systematic Review and Meta-Analysis.

OBJECTIVE: It is not well determined whether liver metastasis is a prognostic factor for survival of metastatic non-small cell lung cancer (NSCLC) patients who received immune checkpoint inhibitors (ICIs). We compared the efficacy of ICIs in patients with NSCLC with or without liver metastases, aiming to evaluate the impact of liver metastasis on survival of NSCLC. METHODS: We systematically searched Pubmed, Embase, and the Cochrane library databases for randomized controlled trials (RCTs) on the efficacy of ICIs in the treatment of NSCLC patients with or without liver metastases. The duration of this search was from January 1, 2000 to June 1, 2022. The reviewers screened the literature, extracted data and conducted quality assessment, and used RevMan 5.4 software and Stata 14 to perform analyses. RESULTS: A total of 17 RCTs were included, published from 2019 to 2022. For NSCLC patients with liver metastases, the risk of disease progression decreased by 36% (HR = 0.64; 95% CI: 0.55-0.75; P < .01) when treated with ICIs, and the death risk (HR = 0.82; 95% CI: 0.72-0.94; P < .01) was also reduced after ICIs treatment. For those without liver metastases, they had significantly improved PFS (HR = 0.56; 95% CI: 0.52-0.60; P < .01) and OS (HR = 0.73; 95% CI: 0.67-0.80; P < .01), compared to those of the control group. Subgroup analysis of OS in liver metastases patients suggested that OS benefit was associated with treatment strategy (for anti-PD-L1 plus chemotherapy versus chemotherapy, HR=1.04; 95% CI: 0.81-1.34; P =.75). CONCLUSION: For NSCLC patients with or without liver metastases, ICIs administration could improve both PFS and OS, especially for those without liver metastases. More RCTs are essential to verify these findings.

Immune checkpoint inhibitors in non-small-cell lung cancer: current status and future directions.

Since 2015, immunotherapies, especially immune checkpoint inhibitors (ICIs), have made great breakthroughs in non-small-cell lung cancer (NSCLC). Among them, nivolumab, pembrolizumab and atezolizumab have been granted US Food and Drug Administration approval for NSCLC. It is imperative to combine ICIs with chemotherapy, radiotherapy, antivascular therapy and targeted therapy. But in the bright future, there are two problems. One is how to use biomarkers to select the beneficiaries. The other is how to achieve a balance between drug effectiveness and safety. There are now seven drugs targeting the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) pathways that have been or are expected to enter clinical treatment. This review focuses on these drugs and summarizes clinical trials that have been reported or that ongoing ones have already entered the recruiting state.

The extracellular vesicles secreted by lung cancer cells in radiation therapy promote endothelial cell angiogenesis by transferring miR-23a.

Angiogenesis is an important factor contributing to the radioresistance of lung cancer. However, the associated mechanisms underlying radiotherapy-induced pro-angiogenesis are unclear. Here, we demonstrated that Extracellular vesicles (EVs) derived from cultured cells in vitro enhanced HUVEC proliferation and migration, and the enhancement effect became more obvious when HUVECs were treated with EV derived from A549 or H1299, two lung cancer cell lines. Additionally, the pro-angiogenesis effect induced by EV could be strengthened when the lung cancer cells were exposed to X-ray irradiation. Furthermore, we verified that the downregulation of PTEN plays a vital role in this process. By evaluating the changes in the levels of microRNAs(miRNAs) targeting PTEN in EV, we found that miR-23a was significantly upregulated and mediated a decrease in PTEN. A luciferase reporter gene transfer experiment demonstrated that PTEN was the direct target of miR-23a, and the kinetics of PTEN expression were opposite to those of miR-23a. Our results show that the miR-23a/PTEN pathway plays an important role in EV-induced angiogenesis. These findings implicate the miR-23a/PTEN axis as a novel therapeutic target for lung cancer radiotherapy.

Endostar enhances the antitumor effects of radiation by affecting energy metabolism and alleviating the tumor microenvironment in a Lewis lung carcinoma mouse model.

Lung cancer is a leading cause of morbidity and mortality. Previous studies have identified that an improvement in treatment efficacy was achieved using Endostar; however, the role of Endostar in lung cancer remains poorly understood. The present study investigated whether the enhanced antitumor effects of Endostar in combination with radiation involved changes in the metabolism and microenvironment in non-small cell lung cancer. A Lewis lung carcinoma mouse model was used, including the control, Endostar (ES), radiotherapy (RT) and Endostar plus radiotherapy (ES + RT) groups. The tumor inhibition rates and growth were described based on changes in tumor volume. In addition, ultraviolet enzymatic analysis was performed to determine the lactate level and reverse transcription-polymerase chain reaction was used to measure the mRNA expression of lactate dehydrogenase (LDH). A Meph-3 pH meter was used to detect the ranges of tumor interstitial tissue pH, and immunohistochemical analysis was adopted to examine hypoxia within the tumor microenvironment. The tumor inhibition rate of the ES + RT group was significantly higher compared with the other three groups (P<0.05). Following treatment, the lactate levels decreased in all three treatment groups compared with the control, particularly in the ES + RT group (P<0.05). Reduced LDH expression and hypoxic fraction in the tumor microenvironment were also observed in the ES + RT group (P<0.05). Furthermore, changes from acidic to alkaline pH in the tumor microenvironment were detected in the ES + RT group. The present study suggested that Endostar is involved in the regulation of metabolism and tumor microenvironment hypoxia, which may be responsible for the enhanced antitumor effect of Endostar in combination with radiotherapy.