Construction of a Lung Adenocarcinoma Prognostic Model Utilizing Serine and Glycine Metabolism-Related Genes.

The objective of this study was to construct a prognostic model by utilizing serine/glycine metabolism-related genes (SGMGs), thus establishing a risk score for lung adenocarcinoma (LUAD). Based on the TCGA-LUAD and SGMG data set, two subtypes with different SGMG expression levels were identified by clustering analysis. Thirteen differential expression genes were used to construct RiskScore by Cox regression. GSE72094 data set was used for validation. The survival characteristics, immune features, and potential benefits of chemotherapy drugs were analyzed for two risk groups. RiskScore was constructed based on the genes ABCC12, RIC3, CYP4B1, SFTPB, CACNA2D2, IGF2BP1, NTSR1, DKK1, CREG2, PITX3, RGS20, FETUB, and IGFBP1. Patients in the low-risk (LR) group exhibited a superior overall survival. In addition, aDCs, iDSs, mast cells, neutrophils, HLA, and type II IFN were more abundant in the LR group with higher IPS scores and lower TIDE scores. In contrast, NK cells, APC coinhibition, and MHC-I were more common in the high-risk (HR) group, which may be more sensitive to chemotherapy drugs such as cisplatin, oxaliplatin, and nilotinib. RiskScore was a promising biomarker that can be used to distinguish LUAD prognosis, immune features, and sensitivity to chemotherapy drugs.

NCAPG stimulates lung adenocarcinoma cell stemness through aerobic glycolysis.

BACKGROUND: Cancer stem cells are pivotal in cancer progression and therapy, including lung adenocarcinoma (LUAD). High NCAPG level is implicated in malignant tumorigenesis, but investigations on NCAPG and LUAD stem cells are warranted. Hence, projecting the impact of NCAPG on cell stemness and the targeted therapy for LUAD is of the essence. METHODS: Bioinformatics analyzed NCAPG expression in LUAD tissues. qRT-PCR assayed NCAPG expression in LUAD cells. CCK-8 assessed cell viability and cell sphere-forming assay measured sphere-forming ability. Western blot assessed expression of stem cell-related markers (CD133, CD44, Oct-4) and specific genes (HK2, PKM2, LDHA) related to glycolysis metabolism pathway. Cellular glycolytic capacity was assayed by glycolytic metabolites pyruvic acid, lactate, citrate, and malate assay kits, and extracellular acidification rate and oxygen consumption rate analyzers. RESULTS: NCAPG was upregulated in LUAD and enriched in the aerobic glycolysis pathway, and its expression was positively correlated with that of glycolytic marker genes. Cell function assays revealed that NCAPG stimulated proliferation, stemness, and glycolytic activity of LUAD cells. Rescue experiments unveiled that 2-DG (glycolysis inhibitor) was able to reverse the stimulative impact of NCAPG overexpression on proliferation, stemness, and glycolytic activity of LUAD cells. CONCLUSION: NCAPG stimulated LUAD cell stemness through activation of glycolysis pathway. NCAPG may be possible biomarker for diagnosis and target for treatment of LUAD.

The Human Positive Cofactor 4 is a Promising Chemotherapeutic Target in Lung Adenocarcinoma.

Reduced sensitivity to chemotherapeutic drugs is almost inevitable in lung adenocarcinoma patients. Thus, understanding the relevant mechanisms is urgent. Positive cofactor 4 (PC4) was at first revealed to be a coactivator of basal transcription. Previous research has shown that PC4 participates in various cellular processes in normal and malignant cells. However, it is still unknown whether PC4 participates in altering the lung adenocarcinoma cell sensitivity to chemotherapy, and the relevant mechanisms remain to be explained. In this study, we discovered that PC4 was overexpressed in cisplatin-resistant lung adenocarcinoma cells. PC4 decreased cisplatin's cytotoxic effects on lung adenocarcinoma in vivo and in vitro. Furthermore, PC4 positively correlated with SOX9 in multiple cancers. PC4 was an upstream regulator of SOX9 in lung adenocarcinoma. Furthermore, PC4 mediated lung adenocarcinoma cell sensitivity to the HIF-PH inhibitor DMOG and the mTOR inhibitor rapamycin, and PC4 mediated the synergistic effect of DMOG and cisplatin. Finally, PC4 destabilized HIF-1α upon cisplatin treatment. Our research showed that PC4 participates in mediating lung adenocarcinoma cell sensitivity to multiple drugs. Mechanistically, PC4 governs multiple downstream pathways associated with chemotherapy resistance, including the SOX9 and HIF-1α pathways. Thus, PC4 is a promising chemotherapeutic target in lung adenocarcinoma.

Cost-effectiveness evaluation of robotic-assisted thoracoscopic surgery versus open thoracotomy and video-assisted thoracoscopic surgery for operable non-small cell lung cancer.

BACKGROUND: This study aimed to evaluate the cost-effectiveness of robotic-assisted thoracoscopic surgery (RATS) over open thoracotomy (OT) and video-assisted thoracoscopic surgery (VATS) for operable non-small cell lung cancer (NSCLC) from the perspective of Chinese healthcare payer. METHODS: The Markov decision model was developed to assess the 5-year costs and quality-adjusted life year (QALY) of RATS versus OT and VATS for operable NSCLC patients. The propensity-matched cohorts were generated from our clinical center to determine the surgical costs and complication rates. An individual patient data meta-analysis was conducted to estimate model probabilities of progression and survival risks. Other model inputs were abstracted from available studies. The primary outcome was incremental cost-effectiveness ratios (ICERs). RESULTS: RATS contributed to an incremental 0.28 QALYs at an additional cost of $3,104.82, making for an ICER of $10,967.41 per QALY versus OT. Robotic approach harvested an incremental 0.05 QALYs at an additional cost of $4006.86, making for an ICER of $80324.98 per QALY over VATS. RATS shown a same cost-effectiveness probability (0.50) versus OT and VATS at a willing-to-pay (WTP) threshold of $12,000 per QALY and $75,800 per QALY, respectively. The probabilities of cost-effectiveness for RATS were 0.64 and 0.21 at a presupposed WTP threshold of $ 30,000 per QALY versus OT and VATS, respectively. CONCLUSIONS: RATS was evaluated to be cost-effective versus OT for patients with operable NSCLC from the perspective of Chinese healthcare payer. To the contrary, robotic approach was associated with less cost-effective than VATS.

Risk factors of conversion in robotic- and video-assisted pulmonary surgery for non-small cell lung cancer.

BACKGROUND: This study aimed to investigate risk factors of conversion to thoracotomy for patients with non-small cell lung cancer (NSCLC) underwent robotic- (RATS) or video-assisted thoracoscopic surgery (VATS). METHODS: A retrospective review was conducted to included consecutive participants from January 2016 to December 2018. Three groups [mini-invasive, conversion, and up-front open thoracotomy (OT) groups] and two series of comparison (conversion versus mini-invasive, and conversion versus OT) were generated. Propensity score-matched analysis (1:1) was conducted to verify outcomes of complications and perioperative factors. Multivariate binary logistic regression analysis was used to identify potential risk factors of conversion. RESULTS: 1177 patients (912 in mini-invasive group, 180 in conversion group, and 85 in OT group) were included. The overall conversion rate was 16.5%. Robotic approach resulted in dramatically lower conversion rate compared to VATS (2.4% vs 25.1%, p < 0.001). After propensity adjustment, no significant difference of complication rates was identified when comparing conversion group with mini-invasive and OT groups. Multivariate regression analyses shown that robotic approach (odd ratio (OR) = 0.037, 95% confidential interval (CI) 0.016-0.087), tumor size < 5 cm (OR = 0.274, 95% CI 0.152-0.493), no chief symptom(OR = 0.311, 95% CI 0.178-0.545), body mass index < 25 kg/m2 (OR = 0.537, 95% CI 0.343-0.842), and lobectomy (OR = 0.079, 95% CI 0.017-0.370) were independent protectors of conversion. CONCLUSIONS: Seven demographic factors might be recognized as independent predictors of conversion. For patients with highly risk of conversion, robotic approach is recommended to perform mini-invasive pulmonary surgery over VATS.

FOXO1 and FOXO3a sensitize non-small-cell lung cancer cells to cisplatin-induced apoptosis independent of Bim.

Low sensitivity to chemotherapy has been a major challenge in the treatment of non-small-cell lung cancer (NSCLC). It is of great clinical significance to discover its mechanisms to improve cell sensitivity to chemotherapeutic drugs. The forkhead box subfamily O (FOXO) transcriptional factors are downstream factors of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway and are reported to play pro-apoptotic roles in a variety of cells including NSCLC cells. But their roles and mechanisms in mediating cell response to chemotherapy remain to be discovered. We proposed that FOXO1 and FOXO3a may increase the sensitivity of NSCLC cells to cisplatin. Moreover, we presumed that LY294002, an inhibitor of the PI3K/AKT pathway, may enhance the cytotoxic effects of cisplatin through upregulating FOXO1 and FOXO3a. In the present study, we found that cisplatin initially increased the expressions and nuclear accumulation of FOXO1 and FOXO3a in NSCLC. Knockdown of FOXO1 and FOXO3a significantly decreased the cell sensitivity to cisplatin in vitro and in vivo. Moreover, inhibition of FOXO1 and FOXO3a attenuated cisplatin-induced cell apoptosis independent of Bim, a pro-apoptotic protein downstream of the FOXOs. Moreover, LY294002 synergistically increased the cytotoxic effects of cisplatin. Mechanistically, LY294002 increased the expressions and nuclear accumulation of FOXO1 and FOXO3a. Knockdown of FOXO1 and FOXO3a abrogated the enhancing effect of LY294002 on cisplatin. Taken together, our results suggested that FOXO1 and FOXO3a sensitize NSCLC cells to cisplatin and mediate the enhancing effects of LY294002 on cisplatin.

Is the presence of lung injury in COVID-19 an independent risk factor for secondary lung cancer?

The morbidity and mortality of lung cancer are increasing. The Corona Virus Disease 2019 (COVID-19) is caused by novel coronavirus 2019-nCoV-2, leading to subsequent pulmonary interstitial fibrosis with chronic inflammatory changes, e.g., inflammatory factors repeatedly continuously stimulating and attacking the alveolar epithelial cells. Meanwhile, 2019-nCoV-2 can activate PI3K/Akt and ERK signaling pathways, which can play the double roles as both anti-inflammatory and carcinogenic factors. Moreover, hypoxemia may be developed, resulting in the up-regulation of HIF-1 α expression, which can be involved in the occurrence, angiogenesis, invasion and metastasis of lung cancer. Additionally, the immune system in 2019-nCoV-2 infected cases can be suppressed to cause tumor immune evasion. Therefore, we speculate that COVID-19 may be a risk factor of secondary lung cancer.

Genomic profiles and transcriptomic microenvironments in 2 patients with synchronous lung adenocarcinoma and lung squamous cell carcinoma: a case report.

BACKGROUND: Multifocal lung cancers (MLCs) are common in patients newly diagnosed with lung cancer, and histological results of most synchronous MLCs are similar. Few cases with different histology findings have been reported, and no genomic or transcriptomic profiling of this kind of cases were done before. Here, we analyzed genomic and transcriptomic profiles of all lung tumors from 2 patients with synchronous adenocarcinoma and squamous cell carcinoma in the same lung lobe. CASE PRESENTATION: Two patients were diagnosed as synchronous adenocarcinoma and squamous cell carcinoma and underwent surgical resection. All 4 tumors showed distinct genomic profiles, therefore were independent primary tumors. Several cancer-associated pathways, such as RTK-RAS pathway and Notch pathway, exhibited different mutated genes in different tumors from the same patient. Several known cancer genes with different mutations, including TP53 and KEAP1, were also detected. Mutation signature analysis demonstrated that the tumor initiation might be related to the transcription coupled nucleotide excision repair process. Two tumors for these 2 patients had loss of heterogeneity (LOH) in HLA genes, showing tumor escaping mechanism. Furthermore, tumor microenvironments showed different patterns in 2 tumors from the same patient. The tumor with more neoantigens and no HLA LOH showed more infiltrating CD8+ T cells and more clonal TCRs, indicating a more active microenvironment. CONCLUSIONS: The lung squamous cell carcinoma and lung adenocarcinoma form the same patient are from independent origins. The genetic profiles and transcriptomic microenvironments are quite different for these 2 tumors. With the same genetic background, the 2 tumors in one patient exhibited different tumor escape mechanisms and immune responses, including HLA LOH and T cell infiltrating and expansion.

Surgery combined with adenoviral p53 gene therapy for treatment of non-small cell lung cancer: a phase II study.

OBJECTIVE: To assess the efficacy of radical surgery combined with recombinant adenoviral human p53 (rAd-p53) gene therapy in treatment of resectable non-small cell lung cancer. METHOD: A total of 163 patients with resectable NSCLC meeting the inclusion criteria were randomly assigned to two groups: radical surgery alone (S) and radical surgery plus surgical wound surface injection of 2 x 1012 rAd-p53 units (SP). All patients were followed up for at least 3 years for efficacy and safety. Study endpoints were loco-regional recurrence or distant metastasis (Rec-Met) rate as primary endpoints, and progression free survival (PFS), overall survival (OS) and safety assessments as secondary endpoints. RESULTS: Recurrence or metastasis (Rec/Met) after surgery were 24/82 (29.27%) in SP group and 37/81 (45.68%) in S group. The difference in the Rec/Met rate was statistically significant (p = 0.0304) by chi-square test. The hazard ratios after adjusting of age and disease stage (S vs. SP) of PFS and OS are 1.772 (95% CI, 1.102 to 2.848) and 2.047 (95% CI, 1.109 to 3.377), respectively. The 3 years PFS and OS for SP vs. S were 71.9% vs. 46.9%, and 88.4% vs. 67.0%, respectively. Differences in PFS and OS between two treatment groups were significant with the p values of 0.0165 and 0.0191, respectively, using Log-Rank test. CONCLUSIONS: The wound surface injection of rAd-p53 showed efficacious effects in preventing recurrence or metastasis and improving PFS and OS after a radical surgery in patients with NSCLC.

Combined analysis of rearrangement of ALK, ROS1, somatic mutation of EGFR, KRAS, BRAF, PIK3CA, and mRNA expression of ERCC1, TYMS, RRM1, TUBB3, EGFR in patients with non-small cell lung cancer and their clinical significance.

PURPOSE: The assessment of single gene such as ERCC1, TYMS, RRM1, TUBB3, EGFR, KRAS, BRAF, PIK3CA, ALK, and ROS1 is now widely applied in therapeutic decisions of non-small cell lung cancer (NSCLC). The aim of our study was to concurrently analyze these genes and evaluate their clinical significance in patients with NSCLC. METHODS: Rearrangement of ALK and ROS1 was analyzed in 120 patients using FISH assays. Somatic mutation of EGFR, KRAS, BRAF, PIK3CA and mRNA expression of ERCC1, TYMS, RRM1, TUBB3, EGFR were examined by liquidchip platform in 350 patients . Data on clinical features were obtained from medical records of 119 patients, and the follow-up was conducted in 106 patients who received platinum-based adjuvant chemotherapy. RESULTS: We identified 5.0% ALK rearrangements, 1.7% ROS1 rearrangements, 36.6% EGFR mutations, 8.9% KRAS mutations, 0% BRAF mutations, and 4.0% PIK3CA mutations. Double or coexisting mutations were identified in 13 patients. Significant correlations were observed among EGFR, KRAS mutation, ERCC1, TYMS, RRM1, TUBB3, EGFR expression, and clinical features, especially histology (P < 0.05). Significant cross-correlations were observed in some pairs of genes (P < 0.05). Patients with low RRM1 expression had a better progression-free survival (PFS) (P < 0.05). Furthermore, EGFR-mutated patients with low RRM1 expression or patients with both ERCC1 and RRM1 low expression had a better PFS (P < 0.05). CONCLUSION: Combined analysis of these commonly studied genes may promote the individual treatment in NSCLC. RRM1 may be a prognostic and predictive biomarker for PFS in patients with NSCLC who received platinum-based adjuvant chemotherapy, and combining EGFR mutation and RRM1 expression or combining ERCC1 and RRM1 expression can enhance prognostic and predictive power for PFS.