TP53 to mediate immune escape in tumor microenvironment: an overview of the research progress.

Increasing evidence suggests that key cancer-causing driver genes continue to exert a sustained influence on the tumor microenvironment (TME), highlighting the importance of immunotherapeutic targeting of gene mutations in governing tumor progression. TP53 is a prominent tumor suppressor that encodes the p53 protein, which controls the initiation and progression of different tumor types. Wild-type p53 maintains cell homeostasis and genomic instability through complex pathways, and mutant p53 (Mut p53) promotes tumor occurrence and development by regulating the TME. To date, it has been wildly considered that TP53 is able to mediate tumor immune escape. Herein, we summarized the relationship between TP53 gene and tumors, discussed the mechanism of Mut p53 mediated tumor immune escape, and summarized the progress of applying p53 protein in immunotherapy. This study will provide a basic basis for further exploration of therapeutic strategies targeting p53 protein.

Knockdown of fascin-1 expression suppresses cell migration and invasion of non-small cell lung cancer by regulating the MAPK pathway.

Fascin-1 is a cytoskeletal protein and it can specifically bind to F-actin, it can be abnormally expressed in a variety of solid tumors. Fascin-1 was identified as a factor for poor prognosis in non-small cell lung cancer (NSCLC). However, the relevant molecular mechanisms are not yet fully understood. In this study, the fascin-1 knockdown cells were produced by lentivirus infection, and then cell proliferation, invasion and cell migration assay were used to investigate the role of fascin-1 in NSCLC cells. The MAPK pathway related proteins were determined by western blot. In the current study, lentivirus-mediated fascin-1 knockdown significantly decreased the proliferation of NSCLC cells. Furthermore, fascin-1 silencing partly inhibited cell invasion and migration. Inhibition of fascin-1 decreased the activity of the MAPK pathway. Therefore, targeting fascin-1 may inhibit the growth and metastasis of NSCLC cells, which is a potentially effective therapeutic strategy for treating NSCLC.

USP10 promotes the progression of triple-negative breast cancer by enhancing the stability of TCF4 protein.

Investigating the role of ubiquitin-specific peptidase 10 (USP10) in triple-negative breast cancer (TNBC). Analyzed USP10 expression levels in tumors using public databases. Detected USP10 mRNA and protein levels in cell lines. Examined USP10 expression in tumor tissues from breast cancer patients. Conducted USP10 knockdown experiments and analyzed changes in cell proliferation and metastasis. Confirmed protein-protein interactions with USP10 through mass spectrometry, Co-IP, and fluorescence experiments. Assessed impact of USP10 on transcription factor 4 (TCF4) ubiquitination and validated TCF4's influence on TNBC cells. We initially identified a pronounced overexpression of USP10 across multiple tumor types, including TNBC. Subsequently, we observed a conspicuous upregulation of USP10 expression levels in breast cancer cell lines compared to normal breast epithelial cells. However, upon subsequent depletion of USP10 within cellular contexts, we noted a substantial attenuation of malignant proliferation and metastatic potential in TNBC cells. In subsequent experimental analyses, we elucidated the physical interaction between USP10 and the transcription factor TCF4, whereby USP10 facilitated the deubiquitination modification of TCF4, consequently promoting its protein stability and contributing to the initiation and progression of TNBC. Collectively, this study demonstrates that USP10 facilitated the deubiquitination modification of TCF4, consequently promoting its protein stability and contributing to the initiation and progression of TNBC.

MYC/MAX-Activated LINC00958 Promotes Lung Adenocarcinoma by Oncogenic Transcriptional Reprogramming Through HOXA1 Activation.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer. The role of the long non-coding RNA (lncRNA) LINC00958, which regulates the malignant behavior of multiple tumors, in LUAD has not been elucidated. METHODS: Tissue microarray, FISH, and qRT-PCR were used to detect the expression of LINC00958. Plasmid and viral infections were used to manipulate gene expression. The role of LINC00958 in LUAD was studied by cell proliferation analysis, cell apoptosis analysis, cell migration and invasion analysis, and subcutaneous inoculation of animal models. At the same time, RNA-Seq, RNA pull-down, ChIRP, ChIP, and luciferase reporter gene assays were performed to clarify the mechanism. RESULTS: The expression of LINC00958 in LUAD tissues was significantly upregulated when compared with that in adjacent tissues and could independently predict poor survival of patients with LUAD. LINC00958 knockdown significantly inhibited the growth and metastasis of lung cancer cells in vitro and in vivo. LINC00958 localized to the nucleus, regulated oncogenes and metabolism-related and immune response-related genes, and interacted with histones. The targets of LINC00958 were TRPV3, STAP2, and EDN2 promoters with motifs of HOXA1, NANOG, FOSL2, JUN, and ATF4. Moreover, HOXA1 overexpression mitigated the LINC00958 knockdown-induced oncogenic phenotype. MYC/MAX motif, which was detected at the cis-element of LINC00958, trans-activated the LINC00958 promoter. CONCLUSIONS: MYC/MAX-trans-activated LINC00958 promotes the malignant behavior of LUAD by recruiting HOXA1 and inducing oncogenic reprogramming.

RAP2A promotes apoptosis resistance of hepatocellular carcinoma cells via the mTOR pathway.

Hepatocellular carcinoma (HCC) is the most common digestive system cancer. In the current study, we investigated the biological effects of Ras-related protein Rap-2a (RAP2A), a GTPase protein, in HCC tissues and cells. We found that RAP2A was upregulated in HCC tissues and cells. RAP2A knockdown could effectively inhibit the proliferation of HCC cells and weaken its apoptosis resistance. In terms of its action mechanism, RAP2A may be involved in activating the mTOR signaling pathway. Therefore, we believe that RAP2A is abnormally highly expressed in HCC tissues and promotes tumor cell proliferation and apoptosis resistance by activating the mTOR signaling pathway, and it may serve as a potential target for HCC treatment.

Clinicopathological significance of fascin-1 expression in patients with non-small cell lung cancer.

PURPOSE: Fascin-1 promotes the formation of filopodia, lamellipodia, and microspikes of cell membrane after its cross-linking with F-actin, thereby enhancing the cell movement and metastasis and invasion of tumor cells. This study explored the fascin-1 protein's expression in non-small cell lung cancer (NSCLC) tissues and its relationship with clinical pathology and prognostic indicators. METHODS: Immunohistochemical analysis was used to determine the expression of fascin-1 in NSCLC tissues. We used quantitative real-time polymerase chain reaction and western blot analysis to further verify the results. The fascin-1 expression and statistical method for clinical pathological parameters are examined by χ (2). Kaplan-Meier method is used for survival analysis. Cox's Proportional Hazard Model was used to conduct a combined-effect analysis for each covariate. RESULTS: In 73 of the 128 cases, NSCLC cancer tissues (57.0%) were found with high expression of fascin-1, which was significantly higher than the adjacent tissues (35/128, 27.3%). The results suggested that the high expression of fascin-1 was significantly correlated with lymph node metastasis (P=0.022) and TNM stage (P=0.042). The high fascin-1 expression patients survived shorter than those NSCLC patients with low fascin-1 expression (P<0.05). Univariate analysis revealed that lymph node metastasis, TNM stage, and fascin-1 expression status were correlated with the overall survival. Similarly, lymph node metastasis, TNM stage, and fascin-1 expression status were significantly associated with the overall survival in multivariate analyses by using the Cox regression model. CONCLUSION: The fascin-1 protein may be a useful prognostic indicator and hopeful new target for NSCLC patients.

Association between the ERCC1 rs11615 polymorphism and clinical outcomes of oxaliplatin-based chemotherapies in gastrointestinal cancer: a meta-analysis.

PURPOSE: The relationship between the excision repair cross-complementing 1 (ERCC1) rs11615 polymorphism (C/T) and responses to oxaliplatin-based chemotherapy for gastric cancer (GC) and colorectal cancer (CRC) patients is controversial. Therefore, we performed a meta-analysis to assess this relationship. METHOD: Relevant studies were retrieved by searching the PubMed database. A systematic review and meta-analysis was performed to evaluate the predictive value of the ERCC1 rs11615 polymorphism for the clinical outcomes of GC and CRC patients receiving oxaliplatin-based chemotherapy. Therapeutic response to chemotherapy, progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: A total of 22 studies were included in this meta-analysis, including 1,242 cases of GC and 1,772 cases of CRC. For the ERCC1 rs11615 polymorphism, the T allele was associated with a reduced response to chemotherapy in Asians and GC patients (P<0.05). On the other hand, the T allele was associated with a significant increase in the risk for shorter PFS and OS in all patients (PFS: hazard ratio [HR] =1.22, P<0.001, 95% confidence interval [CI] =0.93-1.51 and OS: HR =1.12, P<0.001, 95% CI =0.85-1.40). CONCLUSION: The ERCC1 rs11615 polymorphism was closely associated with the clinical outcomes of GC and CRC patients treated with oxaliplatin-based chemotherapy.

The prognostic value of osteopontin expression in non-small cell lung cancer: a meta-analysis.

To investigate the association of Osteopontin (OPN) expression in tumor tissue with clinicopathological features of non-small cell lung carcinoma (NSCLC) patients. Publications assessing the clinicopathological characteristics and prognostic significance of OPN in expression NSCLC were identified up to March 2014. A meta-analysis of eligible studies was performed using standard statistical methods to clarify the association between OPN expression and these clinical parameters. A total of eleven studies met the inclusion criteria, and included 1536 cases of NSCLC tumor tissue and 340 cases of normal lung tissue. The OPN expression rate in NSCLC tissue was higher than normal tissue [Odds ratio (OR) 6.427; 95% confidence interval (CI) 4.689-8.808; P = 0.000]. Simultaneously, we also found that OPN expression was positively associated with stage (OR 0.332; 95% CI 0.250-0.440; P = 0.000), lymph node metastasis (OR 3.094; 95% CI 2.295-4.172; P = 0.000), tumor size (tumor size <3 cm vs. ≥3 cm; OR 0.484; 95% CI 0.303-0.773; P = 0.002) and pathology (OR 0.611; 95% CI 0.466-0.800; P = 0.000). It was unrelated that OPN expression in NSCLC tissue with and degree of differentiation and other clinical features (P > 0.05). Experimental findings indicate that, OPN plays a crucial role in the development of NSCLC.