Increasing evidence indicates that the oncoprotein murine double minute (MDM2) binding protein (MTBP) can be considered a pro-oncogene of human malignancies; however, its function and mechanisms in hepatocellular carcinoma (HCC) are still not clear. In the present work, our results demonstrate that MTBP could function as a co-activator of transcription factor E26 transformation-specific sequence (ETS-1), which plays an important role in HCC cell proliferation and/or metastasis and promotes proliferation of HCC cells. Using luciferase and real-time polymerase chain reaction (qPCR) assays, MTBP was found to enhance the transcription factor activation of ETS-1. The results from chromatin co-immunoprecipitation showed that MTBP enhanced the recruitment of ETS-1 to its downstream gene's (mmp1's) promoter region with ETS-1 binding sites. In cellular and nude mice models, overexpression of MTBP was shown to promote the proliferation of MHCC97-L cells with low endogenous MTBP levels, whereas the knockdown of MTBP led to inhibition of the proliferation of MHCC97-H cells that possessed high endogenous levels of MTBP. The effect of MTBP on ETS-1 was confirmed in the clinical specimens; the expression of MTBP was positively correlated with the downstream genes of ETS-1, mmp3, mmp9, and uPA. Therefore, by establishing the role of MTBP as a novel co-activator of ETS-1, this work expands our knowledge of MTBP or ETS-1 and helps to provide new ideas concerning HCC-related research.

Introduction: The International Federation of Gynecology and Obstetrics (FIGO) staging system is considered the most powerful prognostic factor in patients with cervical cancer. In addition, other surgical-pathological risk factors have been demonstrated to have significance in predicting the prognosis of patients. Therefore, the purpose of this study was to investigate the effects of the FIGO staging system and surgical-pathological risk factors on the prognosis of cervical cancer patients. Methods: A retrospective study was performed on patients diagnosed with cervical cancer at FIGO stage IB1-IIA2. Kaplan-Meier, Cox proportional hazards regression analysis and the support vector machine (SVM) algorithm were used to assess and validate the high-risk factors related to recurrence and death. Results: A total of 647 patients were included. Kaplan-Meier analysis showed that five high-risk factors, including FIGO stage, status of pelvic lymph node, parametrial involvement, tumor size, and depth of cervical cancer, had a significant effect on the prognosis of patients. In multivariate analysis, pelvic lymph node metastasis (hazard ratio [HR] 2.415, 95% confidence interval [CI] 1.471-3.965), parametrial involvement (HR 2.740, 95% CI 1.092-6.872) and >2/3 depth of cervical invasion (HR 2.263, 95% CI 1.045-4.902) were three independent risk factors of disease-free survival. Pelvic lymph node metastasis (HR 3.855, 95% CI 2.125-6.991) and parametrial involvement (HR 3.871, 95% CI 1.375-10.900) were two independent risk factors for overall survival. When all five high-risk factors were assembled and used for classification prediction through SVM, it achieved the highest prediction accuracy of recurrence (accuracy = 69.1%). The highest prediction accuracy for survival was 94.3% when only using the two independent predictors (the pathological status of lymph nodes and parametrium involvement) by SVM classifiers. Among the 13 groups of intermediate-risk factor, the combination of tumor size, histology and grade of differentiation was more accurate in predicting prognosis than the intermediate-risk factors in the Sedlis criteria (recurrence: 86.8% vs. 60.0%; death: 92.0% vs. 71.6%). Conclusions: The combination of FIGO stage and surgical-pathological risk factors can further enhance the prediction accuracy of the prognosis in patients with early-stage cervical cancer. Histology and grade of differentiation can further improve the prediction accuracy of intermediate-risk factors in the Sedlis criteria.

Fibroblast growth factor receptors (FGFRs) modulate numerous cellular processes in tumor cells and tumor microenvironment. However, the effect of FGFRs on tumor prognosis and tumor-infiltrating lymphocytes in gastric cancer (GC) remains controversial.

Background: To investigate the prognostic impact of different types of lymphadenectomy with different extents of tumor resection on the outcomes of stage I non-small-cell lung cancer (NSCLC). Methods: Patients were classified into lobectomy and sublobectomy groups, and then each group was subdivided according to the types of lymphadenectomy. The end points of the study were overall survival (OS) and disease-free survival (DFS). Propensity score matched (PSM) comparative analysis and univariate and multivariate Cox regression analyses were performed. Result: A total of 1,336 patients were included in the current study. Lobectomy was associated with better OS and DFS. In the lobectomy group, lobectomy with bilateral mediastinal lymphadenectomy (BML) was associated with better OS than lobectomy with systematic nodal dissection (SND) or lobe-specific systematic node dissection (L-SND). Lobectomy with SND or L-SND was associated with better OS than lobectomy with systematic nodal sampling (SNS) or selected lymph node biopsy (SLNB). Additionally, lobectomy with BML or SND was associated with better DFS than lobectomy with L-SND or SNS or SLNB. After PSM, compared with lobectomy with SNS or SLNB, lobectomy with SND resulted in more favorable OS and DFS. There was no survival difference between different types of lymphadenectomy for patients who underwent sublobectomy. A multivariable analysis revealed independent associations of lobectomy with BML or SND with better OS and DFS compared with those of lobectomy with SNS or SLNB. Conclusion: This study reveals an association of lobectomy with more systematic and complete lymph node dissection, such as BML or SND, with better prognosis in stage I NSCLC patients.

Despite the expansion of PD-1 checkpoint blockade to multiple types of cancer, whether the programmed cell death 1 (PD-1) expression status on CD8+ tumour infiltrating lymphocytes (TILs) could be a prognostic factor in cervical cancer is still unclear. In this study, we performed ex vivo phenotypic analysis of PD-1 expression on CD8+ TILs by flow cytometry from 47 treatment-naïve cervical cancer patients. With a median follow-up of 26.1 months (95% confidence interval [CI], 24-28.2 months), we then linked the quantitative cellular expression results to progression-free survival and overall survival. Based on the intensity of PD-1 expression, we further categorised the cervical cancer patients into PD-1high expressers (29.8%, 14/47) and PD-1low expressers (70.2%, 33/47). Multivariate analysis revealed that PD-1high expressers are correlated with early recurrence (HR, 5.91; 95% CI, 1.03-33.82; P= 0.046). Univariate analysis also demonstrated that PD-1high expressers are associated with poor overall survival in cervical cancer (HR, 5.365; 95% CI, 1.55-18.6; P=0.008). Moreover, our study also demonstrated that CD8+/CD4+ TIL ratio and HPV infection status are risk factors for early relapse and mortality in cervical cancer patients. In conclusion, this study confirms that PD-1 expression status is an independent prognostic factor for progression free survival in cervical cancer. These findings could be important in predicting the relapse of cervical cancer as a cellular diagnosis method and could be important knowledge for the selection of prospective PD-1 blockade candidates.

The CD71+ erythroid progenitor cells (CECs) exhibit distinctive immunosuppressive properties and regulate antitumor immunity to enable tumor growth. We presented a novel and non-invasive approach to improving immunity by targeting the splenic CECs via sonoporation generated by ultrasound-targeted microbubble destruction (UTMD). The systematic immunity enhanced by the reduction of PDL-1-expressing CECs also benefits the PDL-1 blockade therapy. In the Lewis lung cancer (LLC) model, the study group was treated by UTMD for 10 min at the splenic area with or without anti-mouse PDL-1 intraperitoneal injection. The frequency of splenic CEC, lymphocyte, and cytokine production was analyzed by flow cytometry. Serum interleukin-2 (IL-2) was tested by ELISA. Tumor volume was evaluated by two-dimensional ultrasound. The UTMD treatment consisted of ultrasound sonication and Sonazoid™ microbubble injection through the caudal vein. The mechanic index (MI) of ultrasound was set between 0.98 and 1.03. The results showed a significant reduction of splenic CECs and increased frequency of CD8+ T cells treated by UTMD treatment in the late-stage tumor. Tumor growth could be inhibited by UTMD combined with PDL-1 blockade therapy. The frequencies of interferon-γ (IFN-γ) producing CD8+ and CD4+ T cells were significantly increased after being treated by the combination of UTMD and PDL-1 blockade, while the reactive oxygen species (ROS) production and the fraction of the TGF-β-producing CD11b+ cells were significantly decreased. These preliminary findings suggest that UTMD enhances immune response and facilitates PDL-1 blockade therapy by targeting immunosuppressive CECs in the spleen. Our study provides new aspects and possibilities for treating cancer-related infection and tumor control in oncology.

Nerve growth factor (NGF) is increasingly implicated in cervical cancer progression, but its mechanism in cervical cancer is unclear. Here, studies demonstrate that NGF inhibits the Hippo signaling pathway and activates Yes-associated protein (YAP) to induce cervical cancer cell proliferation and migration. Our results suggested that stimulation of NGF promoted cell growth and migration and activated YAP in HeLa and C-33A cell lines. The expression of YAP target genes (CTGF and ANKRD1) was upregulated after NGF treatment. The NGF inhibitor Ro 08-2750 and siRNA-mediated NGF receptor gene silencing suppressed HeLa and C-33A cells proliferation and migration, activated large suppressor kinase 1 (LATS1) kinase activity, and suppressed YAP function. In addition, the expression of YAP target genes (CTGF and ANKRD1) was suppressed by Ro 08-2750 treatment in HeLa and C-33A cells. Interestingly, proliferation was significantly higher in NGF-treated cells than in control cells, and this effect was completely reversed by the YAP small molecule inhibitor-verteporfin. Furthermore, the mouse xenograft model shows that NGF regulates YAP oncogenic activity in vivo. Mechanistically, NGF stimulation inactivates LATS1 and activates YAP, and NGF inhibition was found to induce large suppressor kinase 1 (LATS1) phosphorylation. Taken together, these data provide the first direct evidence of crosstalk between the NGF signaling and Hippo cancer pathways, an interaction that affects cervical cancer progression. Our study indicates that combined targeting of the NGF signaling and the Hippo pathway represents a novel therapeutic strategy for treatment of cervical cancer.

Malic enzyme 2 (ME2) catalyzes the formation of pyruvate from malic acid and is abnormally expressed in some tumors. However, the exact effects of ME2 on proneural-mesenchymal transition (PMT) and lipogenesis in glioblastoma multiforme (GBM) remain unexplored. Here, we found that ME2 expression was significantly higher in GBM than in normal brain tissues and negatively correlated with overall survival of patients with GBM. Furthermore, we demonstrated that ME2 was positively correlated with mesenchymal features in GBM and promoted proliferation, migration, and invasion of glioma cells. Moreover, ME2 upregulated the expression of mesenchymal markers (N-cadherin, vimentin, YKL40, and MET), whereas it inhibited the expression of proneural maker OLIG2, indicating that ME2 might promote PMT in GBM. We also found that ME2 inhibited the production of mitochondrial reactive oxygen species and AMPK phosphorylation, resulting in SREBP-1 maturation and nuclear localization and enhancing the ACSS2 lipogenesis pathway. Taken together, these results suggest that ME2 promotes PMT and is linked with reprogramming of lipogenesis via AMPK-SREBP-1-ACSS2 signaling in GBM. Therefore, ME2 has potential as a new classification marker in GBM and could provide a new approach to glioma treatment.

c-Src and the epidermal growth factor receptor (EGFR) are key apical kinases that govern cell responses to microenvironmental cues. How c-Src affects EGFR-related signaling and targeted therapy remains elusive. Initially, caspase-8 phosphorylated at tyrosine 380 by c-Src predominantly enhancing c-Src activation to facilitate metastasis through attaining epithelial-mesenchymal transition (EMT) phenotype in lung adenocarcinoma. Mechanistically, the linkage of c-Src SH2 domain with phosphotyrosine 380 of caspase-8 and SH3 domain with "PDEP" motif of caspase-8 overactivates c-Src as compared with other c-Src-partner proteins. c-Src is incapable of triggering EGFR-related signaling. This is reflected by the levels of phosphotyrosine 1068, 1086, and 1145, which have no impact on c-Src activation. Tyrosine kinase inhibitors (TKIs) suppress EGFR-related signaling to yield cell deaths of lung adenocarcinoma by both necroptosis and intrinsic apoptosis. Given that c-Src activation is frequent in lung adenocarcinoma, blocking c-Src activation through dasatinib can seal the survival-signaling-related phosphotyrosines of EGFR by its SH2 domain, which in turn increases the antitumor activity of TKIs in EGFR-mutant lung adenocarcinoma. Collectively, c-Src inactivation by dasatinib administration sensitizes EGFR-mutant lung adenocarcinoma to TKIs.

Colon adenocarcinoma (COAD) accounts for 95% of colon cancer cases, with the 5-year survival rate significantly affected by local or distant metastases. Yiqi Jianpi Huayu Jiedu decoction (YJHJD), based on the theory of "nourish qi, invigorate the spleen, remove blood stasis, and detoxify", has long been applied and shown to be remarkable in the prevention and treatment of gastrointestinal tumors. However, the underlying therapeutic mechanisms of YJHJD have not been fully elucidated. Herein, we first confirmed hsa-miR-374a-3p as a tumor suppressor based on its lower expression in the plasma of patients with COAD with liver metastasis and association with more advanced local progression. We also verified WNT3 as a potential target of hsa-miR-374a-3p and observed its increased expression in COAD tissues. Furthermore, we showed that the hsa-miR-374a-3p/Wnt3/β-catenin axis was responsible for epithelial-mesenchymal transition (EMT) and cellular plasticity in COAD, as well as poorer patient prognosis. Our results showed that YJHJD inhibited motility and colony potential in vitro, as well as liver metastasis of COAD in vivo. Moreover, YJHJD induced a reversal of EMT and cellular plasticity-related molecular expression, increased hsa-miR-374a-3p, and decreased Wnt3 and β-catenin levels. In addition, silencing of hsa-miR-374a-3p weakened YJHJD inhibition, whereas the β-catenin inhibitor XAV939 partially repaired it. Taken together, these results demonstrated that YJHJD suppressed the EMT and cellular plasticity of COAD by regulating hsa-miR-374a-3p/Wnt3/β-catenin signaling.

The worldwide incidence of skin cutaneous melanoma (SKCM) is increasing at a more rapid rate than other tumors. Aberrant alternative splicing (AS) is found to be common in cancer; however, how this process contributes to cancer prognosis still remains largely unknown. Mutations in RNA-binding proteins (RBPs) may trigger great changes in the splicing process. In this study, we comprehensively analyzed DNA and RNA sequencing data and clinical information of SKCM patients, together with widespread changes in splicing patterns induced by RBP mutations. We screened mRNA expression-related and prognosis-related mutations in RBPs and investigated the potential affections of RBP mutations on splicing patterns. Mutations in 853 RBPs were demonstrated to be correlated with splicing aberrations (p < 0.01). Functional enrichment analysis revealed that these alternative splicing events (ASEs) may participate in tumor progress by regulating the modification process, cell-cycle checkpoint, metabolic pathways, MAPK signaling, PI3K-Akt signaling, and other important pathways in cancer. We also constructed a prediction model based on overall survival-related AS events (OS-ASEs) affected by RBP mutations, which exhibited a good predict efficiency with the area under the curve of 0.989. Our work highlights the importance of RBP mutations in splicing alterations and provides effective biomarkers for prediction of prognosis of SKCM.

Phosphorylated CTD-interacting factor 1 (PCIF1) is identified as the only known methyltransferase of N6,2'-O-dimethyladenosine (m6Am) in mRNA. However, its oncogenic and immunogenic role in cancer research is at an initial stage.

Non-alcoholic fatty liver disease (NAFLD) is a risk factor for hepatocellular carcinoma (HCC). However, its carcinogenic mechanism is still unclear, looking for both diseases' transcriptome levels, the same changes as we are looking for NAFLD may provide a potential mechanism of action of HCC. Thus, our study aimed to discover the coexisting pathogenic genes of NAFLD and HCC.

Circulating cell-free DNA (cfDNA) level has been demonstrated to be associated with efficacy in first generation EGFR TKIs in non-small cell lung cancer (NSCLC). However, the role of dynamic cfDNA analysis using next-generation sequencing (NGS) in patients with subsequent third-generation EGFR TKIs remains unclear.

Background and Purpose: Lymph node status is a key factor for the recommendation of organ preservation for patients with locally advanced rectal cancer (LARC) following neoadjuvant therapy but generally confirmed post-operation. This study aimed to preoperatively predict the lymph node status following neoadjuvant therapy using multiparametric magnetic resonance imaging (MRI)-based radiomic signature. Materials and Methods: A total of 391 patients with LARC who underwent neoadjuvant therapy and TME were included, of which 261 and 130 patients were allocated to the primary cohort and the validation cohort, respectively. The tumor area, as determined by preoperative MRI, underwent radiomics analysis to build a radiomic signature related to lymph node status. Two radiologists reassessed the lymph node status on MRI. The radiomic signature and restaging results were included in a multivariate analysis to build a combined model for predicting the lymph node status. Stratified analyses were performed to test the predictive ability of the combined model in patients with post-therapeutic MRI T1-2 or T3-4 tumors, respectively. Results: The combined model was built in the primary cohort, and predicted lymph node metastasis (LNM+) with an area under the curve of 0.818 and a negative predictive value (NPV) of 93.7% were considered in the validation cohort. Stratified analyses indicated that the combined model could predict LNM+ with a NPV of 100 and 87.8% in the post-therapeutic MRI T1-2 and T3-4 subgroups, respectively. Conclusion: This study reveals the potential of radiomics as a predictor of lymph node status for patients with LARC following neoadjuvant therapy, especially for those with post-therapeutic MRI T1-2 tumors.

Tyrosine phosphatase receptor type N (PTPRN) plays an important role in the regulation of the secretion pathways of various neuroendocrine cells. Moreover, PTPRN was demonstrated to play a crucial role in the initiation and progression of the signalling cascade regulating cell function. In this study, fifty-seven glioma patients were enrolled for clinical and prognostic analyses. The cell phenotype was determined by cell proliferation and migration assays. RNA-seq, co-IP and mass spectrometry were used to study the molecular mechanism of the effects of PTPRN on cell proliferation and metastasis. The result showed that High expression of PTPRN indicated a poor prognosis of high-grade glioma. PTPRN downregulation reduced the proliferation and migration of glioma cells, and PTPRN overexpression induced the proliferation and migration of glioma cells. PTPRN knockdown decreased tumor growth in a mouse xenograft model. Effect of PTPRN knockdown on the transcriptome was studied in U87 glioma cells. PTPRN activated the PI3K/AKT pathway by interacting with HSP90AA1. In conclusion, PTPRN is an important proliferation- and metastasis-promoting factor. Reducing the expression of PTPRN in glioma cells can be used as a potential therapeutic strategy.

Lung adenocarcinoma (LUAD) is the most common histological lung cancer, and it is the leading cause of cancer-related deaths worldwide. LncRNA-AL139385.1 (ENSG00000275880) is a novel lncRNA that is abnormally expressed in various cancer types including LUAD. However, the underlying biological function and potential mechanisms of AL139385.1 driving the progression of LUAD remain unclear. In this study, we investigated the role of AL139385.1 in LUAD and found that DNA hypomethylation was positively correlated with AL139385.1 expression in LUAD. Moreover, we uncover that the expression of AL139385.1 in LUAD tissues was significantly higher than that of AL139385.1 expression in adjacent normal tissues. Kaplan-Meier survival analysis showed that patients with higher AL139385.1 expression correlated with adverse overall survival and progression-free survival. Receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) value of AL139385.1 was 0.808. Correlation analysis showed that AL139385.1 expression was associated with immune infiltration in LUAD. We also found that AL139385.1 was upregulated in LUAD cancer tissues and cell lines. Knockdown of AL139385.1 significantly inhibited cell proliferation and migration abilities of LUAD. Finally, we constructed a ceRNA network that includes hsa-miR-532-5p and four mRNAs (GALNT3, CYCS, EIF5A, and ITGB4) specific to AL139385.1 in LUAD. Subsequent Kaplan-Meier survival analysis suggested that polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), cytochrome c, somatic (CYCS), eukaryotic translation initiation factor 5A (EIF5A), and integrin subunit beta 4 (ITGB4), were potential prognostic biomarkers for patients with LUAD. In conclusion, this finding provides possible mechanisms underlying the abnormal upregulation of AL139385.1 as well as a comprehensive view of the AL139385.1-mediated competing endogenous RNAs (ceRNA) network in LUAD, thereby highlighting its potential role in diagnosis and therapy.

Gliomas account for 75% of all primary malignant brain tumors in adults and are associated with high mortality. Mounting evidence has shown that NCAPG2 is differentially expressed in various cancers. However, the prognostic value and immune functions of NCAPG2 in low-grade glioma (LGG) remain unresolved. In the present study, we revealed that NCAPG2 was up-regulated in LGG, and its higher expression was associated with adverse clinical outcomes and poor clinical characteristics, including WHO grade, IDH mutation, 1p/19q codeletion, and primary therapy outcome. The results of the Cox regression analysis revealed that NCAPG2 was an independent factor for the prognosis of low-grade glioma. Meanwhile, we also established a nomogram based on NCAPG2 to predict the 1-, 3-, or 5-year survival in LGG patients. Furthermore, we found that Copy number variation (CNV) and DNA hypomethylation results in its overexpression in LGG. In addition, functional annotation confirmed that NCAPG2 was mainly involved in the immune regulation and WNT signaling pathways. Finally, we determined that increased expression of NCAPG2 was correlated with infiltration levels of various immune cells and immune checkpoint in LGG. Importantly, we found that NCAPG2 was highly expressed in glioma stem cells lines and knockdown of NCAPG2 significantly inhibited the self-renewal ability of GSC. This is the first study to identify NCAPG2 as a new potential prognostic biomarker and characterize the functional roles of NCAPG2 in the progression of LGG, and provides a novel potential diagnostic and therapeutic biomarker for LGG in the future.

The lung immune prognostic index (LIPI) has been shown to be an important prognostic marker for various tumors. However, the prognostic value of LIPI among non-small cell lung cancer (NSCLC) patients treated with systemic therapy remains controversial. We aimed to evaluate survival status according to LIPI among NSCLC patients receiving different forms of systemic therapy at our institution. We also performed a meta-analysis of articles from PubMed and Embase to illustrate this question. For our cohort, we found that good LIPI was associated with better overall survival (OS) among 91 patients on immunotherapy, 329 patients on targeted therapy, and 570 patients on chemotherapy. For the meta-analysis, a total of eight studies with 8,721 patients were included. Pooled results showed that a higher LIPI (those with 1 or 2 factors) was associated with poor overall progression-free survival (PFS) (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.45-1.71) and OS (HR, 2.01; 95% CI, 1.75-2.31). Subgroup analyses showed that a higher LIPI was related to poor survival among patients prescribed different systemic therapies: immunotherapy (OS HR, 2.50; 95% CI, 1.99-3.13; PFS HR, 1.77; 95% CI, 1.56-2.01), chemotherapy (OS HR, 1.58; 95% CI, 1.34-1.86; PFS HR, 1.38; 95% CI, 1.23-1.55), and targeted therapy (OS HR; 2.15, 95% CI, 1.57-2.96; PFS HR, 1.60; 95% CI, 1.25-2.06). The study shows that the LIPI is a clinically significant prognostic factor for NSCLC patients receiving systemic therapy.

Dysregulation of cytokines and growth factors is a general feature of tumor microenvironment, and unraveling the expression spectrum of cytokine and growth factor in niche is of utmost importance. Here, we evaluated cytokine profiling of bone marrow serum samples in AML patients and healthy controls. Protein expression profiling of serum from nine AML patients and five healthy controls was obtained using a biotinylated antibody chip. A total of 507 cytokines and growth factors were analyzed. Compared with healthy people, AML patients expressed 31 signature proteins, among which, 27 were significantly higher expressed and 4 proteins were lower. When patients were divided into favorable and poor prognosis, 12 signature proteins were significantly differentially expressed between these two groups. Furthermore, in order to identify the accuracy of cytokine expression profiles, we verified and analyzed the expression of THBS1 (Thrombospondin 1) in 116 patients and 9 healthy people. We found that THBS1 was lowly expressed in AML patients, which might be induced by promoter methylation, and patients with low THBS1 possessed shorter survivor time. Our data indicated that we successfully unveil differentially expressed proteins in AML patients using a biotinylated antibody chip; among them, THBS1 may be a potential therapeutic target for AML patients' treatment.