Promotes Tumor Cell Proliferation Research Articles

C-Terminal Truncated HBx Facilitates Oncogenesis by Modulating Cell Cycle and Glucose Metabolism in FXR-Deficient Hepatocellular Carcinoma

Farnesoid X receptor (FXR) is a nuclear receptor known to play protective roles in anti-hepatocarcinogenesis and regulation of the basal metabolism of glucose, lipids, and bile acids. FXR expression is low or absent in HBV-associated hepatocarcinogenesis. Full-length HBx and HBx C-terminal truncation are frequently found in clinical HCC samples and play distinct roles in hepatocarcinogenesis by interacting with FXR or FXR signaling. However, the impact of C-terminal truncated HBx on the progression of hepatocarcinogenesis in the absence of FXR is unclear. In this study, we found that one known FXR binding protein, a C-terminal truncated X protein (HBx C40) enhanced obviously and promoted tumor cell proliferation and migration by altering cell cycle distribution and inducing apoptosis in the absence of FXR. HBx C40 enhanced the growth of FXR-deficient tumors in vivo. In addition, RNA-sequencing analysis showed that HBx C40 overexpression could affect energy metabolism. Overexpressed HSPB8 aggravated the metabolic reprogramming induced by down-regulating glucose metabolism-associated hexokinase 2 genes in HBx C40-induced hepatocarcinogenesis. Overall, our study suggests that C-terminal truncated HBx C40 synergizes with FXR deficiency by altering cell cycle distribution as well as disturbing glucose metabolism to promote HCC development.

Transferred mitochondria accumulate reactive oxygen species, promoting proliferation.

Recent studies reveal that lateral mitochondrial transfer, the movement of mitochondria from one cell to another, can affect cellular and tissue homeostasis. Most of what we know about mitochondrial transfer stems from bulk cell studies and have led to the paradigm that functional transferred mitochondria restore bioenergetics and revitalize cellular functions to recipient cells with damaged or non-functional mitochondrial networks. However, we show that mitochondrial transfer also occurs between cells with functioning endogenous mitochondrial networks, but the mechanisms underlying how transferred mitochondria can promote such sustained behavioral reprogramming remain unclear. We report that unexpectedly, transferred macrophage mitochondria are dysfunctional and accumulate reactive oxygen species in recipient cancer cells. We further discovered that reactive oxygen species accumulation activates ERK signaling, promoting cancer cell proliferation. Pro-tumorigenic macrophages exhibit fragmented mitochondrial networks, leading to higher rates of mitochondrial transfer to cancer cells. Finally, we observe that macrophage mitochondrial transfer promotes tumor cell proliferation in vivo. Collectively these results indicate that transferred macrophage mitochondria activate downstream signaling pathways in a ROS-dependent manner in cancer cells, and provide a model of how sustained behavioral reprogramming can be mediated by a relatively small amount of transferred mitochondria in vitro and in vivo.

Abstract P1-13-05: Extracellular vesicles-transported lncRNA BCDR1 promotes tumor cell proliferation and therapy resistance via upregulating G1/S-phase transition in breast cancer

Abstract Background Extracellular vesicles (EVs), secreted by tumor cells for intercellular communication, play an important role in breast cancer progression. Previous studies have proved that lncRNA could use EVs to transmit signals and affect the progression and treatment of breast cancer. In addition, a previous study has found that, in HER2 therapy-resistant tumors, CDK4/6 activity and cell cycle progression genes were involved and might serve as treatment targets. However, recent clinical trials were not supportive of the use of CDK4/6 inhibitors in HER2 enriched internal subtypes of breast cancer. In this study, we aim to explore the role of EVs-transported long noncoding RNA BCDR1 in the promotion of cell cycle progression in HER2-positive breast cancer, exploring a new potential target in combination with CDK4/6 inhibitor and anti-HER2 treatment. Methods Samples were collected from patients with HER2 overexpression receiving neoadjuvant therapy. RNA-seq was performed to identify differentially expressed RNAs between pathological complete response (pCR) and non-pCR group. In addition, serum extracellular vesicles were collected and determined through RNA-seq. The drug response and proliferation rate of tumor cells were measured in breast cancer cells (HCC-1954, BT-474 and MCF-7). Quantitative RT-PCR (qRT-PCR) was used to detect the expression levels of BCDR1 and its potential target genes. RNA-seq and GSEA analysis was carried out to determine the target pathways regulated by BCDR1. DNA fiber assay, mass spectrometry, and flow cytometry were used to understand the underlying mechanism of BCDR1. Results Core needle biopsy tissues from HER2-positive breast cancer patients with any ER status were collected before NAC. Among genes differentially overexpressed, BCDR1 was found to be downregulated in pCR group compared with non-pCR group. BCDR1 was also elevated in plasma EVs in the non-pCR group. In addition, overexpression of BCDR1 in breast cancer cells promoted cell proliferation and HER2 treatment resistance. Through pathway analysis, we found BCDR1 could facilitate G1/S-phase transition. Flow cytometry confirmed these findings. We also noticed that proteins that regulate DNA licensing including minichromosome maintenance proteins (MCMs) were enriched in BCDR1 overexpression cells. Through DNA fiber assay, we confirmed that BCDR1 could promote DNA replication initiation. Interestingly, under CDK4/6 inhibitor treatment, BCDR1 was induced, unrevealing an internal treatment-resistant mechanism in these tumor cells. Through EVs RT-qPCR, we found BCDR1 could transport from high expression cells to low, with the same biological function. We also explored antisense oligonucleotide (ASO) use in the inhibition of BCDR1 biological function and transportation. Conclusion BCDR1 promotes cell proliferation and therapy resistance via upregulating DNA licensing in breast cancer. BCDR1 could transported through EVs with same biological function. This study also suggests that BCDR1 could serve as a biomarker and therapeutic target in breast cancer. Citation Format: Qi Zhang, Bingqiu Xiu, Yayun Chi, Jiong Wu. Extracellular vesicles-transported lncRNA BCDR1 promotes tumor cell proliferation and therapy resistance via upregulating G1/S-phase transition in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-05.

Integrative analysis of bulk and single-cell gene expression profiles to identify tumor-associated macrophage-derived CCL18 as a therapeutic target of esophageal squamous cell carcinoma

BackgroundEsophageal squamous cell carcinoma (ESCC) is a common gastrointestinal malignancy with poor patient prognosis. Current treatment for ESCC, including immunotherapy, is only beneficial for a small subset of patients. Better characterization of the tumor microenvironment (TME) and the development of novel therapeutic targets are urgently needed.MethodsIn the present study, we hypothesized that integration of single-cell transcriptomic sequencing and large microarray sequencing of ESCC biopsies would reveal the key cell subtypes and therapeutic targets that determine the prognostic and tumorigenesis of ESCC. We characterized the gene expression profiles, gene sets enrichment, and the TME landscape of a microarray cohort including 84 ESCC tumors and their paired peritumor samples. We integrated single-cell transcriptomic sequencing and bulk microarray sequencing of ESCC to reveal key cell subtypes and druggable targets that determine the prognostic and tumorigenesis of ESCC. We then designed and screened a blocking peptide targeting Chemokine C–C motif ligand 18 (CCL18) derived from tumor associated macrophages and validated its potency by MTT assay. The antitumor activity of CCL18 blocking peptide was validated in vivo by using 4-nitroquinoline-1-oxide (4-NQO) induced spontaneous ESCC mouse model.ResultsComparative gene expression and cell–cell interaction analyses revealed dysregulated chemokine and cytokine pathways during ESCC carcinogenesis. TME deconvolution and cell interaction analyses allow us to identify the chemokine CCL18 secreted by tumor associated macrophages could promote tumor cell proliferation via JAK2/STAT3 signaling pathway and lead to poor prognosis of ESCC. The peptide Pep3 could inhibit the proliferation of EC-109 cells promoted by CCL18 and significantly restrain the tumor progression in 4-NQO-induced spontaneous ESCC mouse model.ConclusionsFor the first time, we discovered and validated that CCL18 blockade could significantly prevent ESCC progression. Our study revealed the comprehensive cell–cell interaction network in the TME of ESCC and provided novel therapeutic targets and strategies to ESCC treatment.

Budding uninhibited by benzimidazoles 1 overexpression is associated with poor prognosis and malignant phenotype: A promising therapeutic target for lung adenocarcinoma.

The budding uninhibited by benzimidazoles (BUB) family is involved in the cell cycle process as mitotic checkpoint components. Abnormal proliferation is a vital process in the development of lung adenocarcinoma (LUAD). Nevertheless, the roles of BUB1 in LUAD remain unclear. In this study, we evaluated the prognostic value and biological functions of BUB1 in LUAD using data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), clinical LUAD samples, and in vitro experiments. The expression, prognostic significance, functions, immune infiltration, and methylation of BUB1 in LUAD were comprehensively analyzed using TCGA, GEO, Gene Expression Profiling Interactive Analysis, Metascape, cBioPortal, MethSurv, and cancerSEA databases. Furthermore, we performed a battery of in vitro experiments and immunohistochemistry (IHC) to verify the bioinformatics results. Multivariate analysis revealed that BUB1 overexpression was an independent prognostic factor (hazard ratio=1.499, p=0.013). Functional enrichment analysis showed that BUB1 was correlated with cell cycle, proliferation, DNA repair, DNA damage, and invasion (p < 0.05). Finally, in vitro experiments showed that downregulation of BUB1 inhibited the proliferation, migration, and invasion of LUAD cells and promoted LUAD cell apoptosis. IHC also showed that BUB1 was overexpressed in LUAD (p < 0.001) and was significantly associated with poor prognosis (p < 0.001). Our bioinformatics and IHC analyses revealed that BUB1 overexpression was an adverse prognostic factor in LUAD. In vitro experiments demonstrated that BUB1 promoted tumor cell proliferation, migration, and invasion in LUAD. These results indicated that BUB1 was a promising biomarker and potential therapeutic target in LUAD.

A phase 1b/2 study of batiraxcept (AVB-S6-500) in combination with cabozantinib in patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC).

666 Background: Activation of the GAS6/AXL pathway promotes tumor cell proliferation; high levels of GAS6 and AXL have been associated with drug resistance and decreased survival. Batiraxcept is an ultra-high affinity decoy protein that captures GAS6, preventing it from activating AXL signaling. Serum soluble AXL (sAXL)/GAS6 ratio correlates with response to batiraxcept in advanced ovarian cancer. Batiraxcept in combination with cabozantinib is being evaluated in patients (pts) with metastatic clear cell renal cell carcinoma (ccRCC) in this study. Prior studies of cabozantinib in similar pt populations have shown an overall response rate (ORR) ranging from 15 – 32.5% and progression-free survival (PFS) from 3.7-7.2 months (mo). Methods: Key eligibility criteria include previously treated ccRCC pts, excluding prior cabozantinib. Objectives were to determine the safety of batiraxcept plus cabozantinib 60 mg, the recommended phase 2 dose (RP2D), ORR, PFS, duration of response. Correlative endpoints included assessment of baseline serum sAXL/GAS6 with ORR and PFS. Results: In Phase 1b (P1b), 26 pts received at least one dose of batiraxcept with cabozantinib (16 pts - 15 mg/kg; 10 pts - 20 mg/kg). Median age was 60 (range 40-81), male 85% (n=22), IMDC intermediate/poor risk 77% (n=20). All pts received prior immuno-oncology (IO) therapy, 54% (n=14) also received VEGF-TKI; 85% (n=22) received 1 to 2 prior lines of therapy (range 1-6). Median follow-up time was 11.6 mo (range 3.7-18). The RP2D is 15 mg/kg. Related adverse events (AE) any grade and grade ≥ 3 were 100% and 39% (n=10), respectively. Cabozantinib dose reductions occurred in 54% (n=14). AEs of special interest were grade 1 or 2 infusion related reactions, 27% (n=7). Batiraxcept was discontinued due to disease progression 62% (n=16) or toxicity 12% (n=3). The table shows P1b efficacy, ORR of 42%, median PFS of 9.3 mo, and DCR of 84%. Twenty (77%) pts had high baseline sAXL/GAS6 levels; ORR was 55% (11/20) with mPFS of 9.3 mo, compared to 0% ORR and mPFS 6.4 mo in the low sAXL/GAS6 pts. Conclusions: Batiraxcept was well tolerated when combined with cabozantinib. No new safety signals were noted. Efficacy for the combination is encouraging compared to historical cabozantinib monotherapy data. Higher GAS6 levels were predictive for treatment response. The P2 accrual is complete and efficacy data are maturing. A P3 trial plans to evaluate the efficacy in ccRCC patients who have progressed on IO-based and VEGF-TKI therapies. Clinical trial information: NCT04300140 . [Table: see text]

SEMA5A-PLXNB3 Axis Promotes PDAC Liver Metastasis Outgrowth through Enhancing the Warburg Effect.

Patients bearing liver metastasis of pancreatic adeno carcinoma (PDAC) suffer from poor prognosis due to its short duration and high mortality. Complex tumor microenvironment (TME) exists in liver metastatic niches, and tumor-associated macrophages (TAMs) have play vital roles in metastasis generation and outgrowth. We have discovered that M2 type TAM-derived SEMA5A could bind to its tumor cell-expressed receptor PLXNB3 to promote tumor cell proliferation and outgrowth. We utilized liver metastasis samples of PDAC patients, intrasplenic injection mouse models, and Kras G12D/Trp53 R172H/Pdx1-Cre (KPC) mouse models for in vivo study. In mechanism investigation, we have discovered that SEMA5A-PLXNB3 axis could achieve tumor cell proliferation and survival via enhancing aerobic glycolysis termed as the Warburg effects. Targeting this axis may be a potential therapeutic approach for PDAC patients with unresectable liver metastasis.

Multi-omics analysis of N6-methyladenosine reader IGF2BP3 as a promising biomarker in pan-cancer.

Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) has been reported to exhibit an oncogenic effect as an RNA-binding protein (RBP) by promoting tumor cell proliferation, migration and invasion in several tumor types. However, a pan-cancer analysis of IGF2BP3 is not currently available, and the exact roles of IGF2BP3 in prognosis and immunology in cancer patients remain enigmatic. The main aim of this study was to provide visualization of the systemic prognostic landscape of IGF2BP3 in pan-cancer and to uncover the potential relationship between IGF2BP3 expression in the tumor microenvironment and immune infiltration profile. Raw data on IGF2BP3 expression were obtained from GTEx, CCLE, TCGA, and HPA data portals. We have investigated the expression patterns, diagnostic and prognostic significance, mutation landscapes, functional analysis, and functional states of IGF2BP3 utilizing multiple databases, including HPA, TISIDB, cBioPortal, GeneMANIA, GESA, and CancerSEA. Moreover, the relationship of IGF2BP3 expression with immune infiltrates, TMB, MSI and immune-related genes was evaluated in pan-cancer. IGF2BP3 with drug sensitivity analysis was performed from the CellMiner database. Furthermore, the expression of IGF2BP3 in different grades of glioma was detected by immunohistochemical staining and western blot. We found that IGF2BP3 was ubiquitously highly expressed in pan-cancer and significantly correlated with diagnosis, prognosis, TMB, MSI, and drug sensitivity in various types of cancer. Besides, IGF2BP3 was involved in many cancer pathways and varied in different immune and molecular subtypes of cancers. Additionally, IGF2BP3 is critically associated with genetic markers of immunomodulators in various cancers. Finally, we validated that IGF2BP3 protein expression was significantly higher in glioma than in normal tissue, especially in GBM. IGF2BP3 may be a potential molecular biomarker for diagnosis and prognosis in pan-cancer, especially for glioma. It could become a novel therapeutic target for various cancers.

M7G-related gene NUDT4 as a novel biomarker promoting cancer cell proliferation in lung adenocarcinoma.

Lung cancer is the leading cause of mortality in cancer patients. N7-methylguanosine (m7G) modification as a translational regulation pattern has been reported to participate in multiple types of cancer progression, but little is known in lung cancer. This study attempts to explore the role of m7G-related proteins in genetic and epigenetic variations in lung adenocarcinoma, and its relationship with clinical prognosis, immune infiltration, and immunotherapy. Sequencing data were obtained from the Genomic Data Commons (GDC) Data Portal and Gene Expression Omnibus (GEO) databases. Consensus clustering was utilized to distinguish m7G clusters, and responses to immunotherapy were also evaluated. Moreover, univariate and multivariate Cox and Least absolute shrinkage and selection operator LASSO Cox regression analyses were used to screen independent prognostic factors and generated risk scores for constructing a survival prediction model. Multiple cell types such as epithelial cells and immune cells were identified to verify the bulk RNA results. Short hairpin RNA (shRNA) Tet-on plasmids, Clustered Regularly Interspaced Short Palindromic Repeats CRISPR/Cas9 for knockout plasmids, and nucleoside diphosphate linked to moiety X-type motif 4 (NUDT4) overexpression plasmids were constructed to inhibit or promote tumor cell NUDT4 expression, then RT-qPCR, Cell Counting Kit-8 CCK8 proliferation assay, and Transwell assay were used to observe tumor cell biological functions. Fifteen m7G-related genes were highly expressed in tumor samples, and 12 genes were associated with poor prognosis. m7G cluster-B had lower immune infiltration level, worse survival, and samples that predicted poor responses to immunotherapy. The multivariate Cox model showed that NUDT4 and WDR4 (WD repeat domain 4) were independent risk factors. Single-cell m7G gene set variation analysis (GSVA) scores also had a negative correlation tendency with immune infiltration level and T-cell Programmed Death-1 PD-1 expression, but the statistics were not significant. Knocking down and knocking out the NUDT4 expression significantly inhibited cell proliferation capability in A549 and H1299 cells. In contrast, overexpressing NUDT4 promoted tumor cell proliferation. However, there was no difference in migration capability in the knockdown, knockout, or overexpression groups. Our study revealed that m7G modification-related proteins are closely related to the tumor microenvironment, immune cell infiltration, responses to immunotherapy, and patients' prognosis in lung adenocarcinoma and could be useful biomarkers for the identification of patients who could benefit from immunotherapy. The m7G modification protein NUDT4 may be a novel biomarker in promoting the progression of lung cancer.

Abstract B013: Tumor-derived CCL5 recruits’ cancer-associated fibroblasts and promotes tumor cell proliferation in esophageal carcinomas

Abstract The tumor microenvironment (TME), at both the primary tumor and sites of metastases, is a key determinant in the success of metastatic colonization. Cancer-associated fibroblasts (CAFs) are a predominant cell type in the TME that, through deposition and remodeling of extracellular matrix (ECM) components, can mediate the TME and promote cancer progression. In addition to cancer progression and metastasis, CAFs have also been shown to mediate resistance to chemotherapy and radiotherapy. Therefore, there is a need to identify the factors which activate and recruit CAFs to solid tumors. Though cytokine arrays, we identified CC motif chemokine ligand 5 (CCL5) as a secreted factor which is increased upon co-culture of esophageal cancer cell lines and CAFs. Using CRISPR/Cas9 technology, we determined that CCL5 is predominantly tumor-cell derived and loss of tumor-cell derived CCL5 reduced esophageal carcinoma cell proliferation in vitro and in vivo. We propose that this reduction in cell proliferation is mediated by ERK1/2 signaling as loss of tumor-cell derived CCL5 reduces expression of p-ERK1/2 and cyclin D1, an ERK1/2 target gene which is essential for cell cycle progression. Interestingly, the loss of tumor-derived CCL5 also reduced the percentage of CAFs, identified by αSMA positivity, recruited to xenograft tumors in vivo. CCL5 is a ligand for the CC motif receptor 5 (CCR5), for which a clinically approved inhibitor exists called Maraviroc. We treated xenografts generated from esophageal carcinoma cell lines or patient derived tumor fragments with Maraviroc. Maraviroc treated xenografts had reduced tumor volume, CAF recruitment and ERK1/2 signaling. Thus, mimicking the effects of the genetic loss of CCL5. Analysis of the TCGA database, identified that high CCL5 or CCR5 expression is associated with poorer prognosis in low grade esophageal carcinomas. Together, we propose that this data highlights the importance of CCL5 in esophageal carcinomas with regards to CAF recruitment and tumor cell proliferation, and that the maraviroc in vivo experiments suggest that targeting the CCL5-CCR5 axis may have therapeutic potential in esophageal carcinomas. Citation Format: Karen J. Dunbar, Qiaosi Tang, Tatiana A. Karakasheva, Anil K. Rustgi. Tumor-derived CCL5 recruits’ cancer-associated fibroblasts and promotes tumor cell proliferation in esophageal carcinomas [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B013.

Long non-coding RNA FAM239A promotes tumor cell proliferation and migration by regulating tyrosine phosphatase Src homology 2 domain-containing phosphatase 2 in head and neck squamous cell carcinoma

ObjectiveHead and neck squamous cell carcinoma (HNSCC), is one of the malignant tumors with high recurrence and metastasis. The family with sequence similarity (FAM) of non-coding RNAs promoted tumorigenesis and metastasis. But so far, long non-coding RNA (lncRNA) FAM239A’s function in HNSCC regulation remains unclear. This study aimed to explore the lncRNA FAM239A function and regulation mechanism in HNSCC cell proliferation and migration. DesignThe expression level of lncRNA FAM239A and tyrosine phosphatase Src homology 2 domain-containing phosphatase 2 (SHP2) in HNSCC tumor tissue was tested by quantitative polymerase chain reaction. The cell proliferation and migration were tested by cell counting kit 8, kinetic live cell assay, and wound healing assay. The differential expression of SHP2 and immune infiltration in HNSCC were analyzed in the tumor immune estimation response and human protein atlas databases. And the survival analysis of SHP2 in HNSCC was analyzed in the gene expression profiling interactive analysis 2 databases. The SHP2 expression was tested by western blotting when lncRNA FAM239A overexpression and knockdown. ResultsLncRNA FAM239A and SHP2 were ectopically expressed in HNSCC tumor tissue. Cell proliferation and wound healing assays showed that lncRNA FAM239A promoted tumor cell proliferation and migration. SHP2 was overexpressed in HNSCC tumor tissue by database analyses, and the higher SHP2 expression caused poorer overall survival and disease-free survival in HNSCC patients. SHP2 expression was positively regulated by lncRNA FAM239A. ConclusionsLncRNA FAM239A promoted HNSCC cell proliferation and migration through upregulating SHP2 expression, which potentially provided new regulators for HNSCC.

HSF1 expression in tumor-associated macrophages promotes tumor cell proliferation and indicates poor prognosis in esophageal squamous cell carcinoma.

Tumor-associated macrophages (TAMs), are crucial for the survival and development of tumor cells. Heat shock factor 1 (HSF1) is a potent, complex carcinogenesis modulator, and esophageal cancer (EC) patients have a bad prognosis when HSF1 is highly expressed. HSF1's clinical importance and biological role in TAMs are still unknown. The HSF1 expression profile and patient survival information were analyzed from the TCGA database. The infiltration of different types of immune cells in EC was evaluated based on HSF1 gene expression by Sangerbox 3.0. Immunochemistry was employed to assess HSF1 protein expression in 134 individuals with esophageal squamous cell carcinoma (ESCC), proceeded by association with clinicopathological variables. The role of macrophage-driven HSF1 were observed using HSF1-knockdown THP1 cells. High level of HSF1 have a poorer prognosis in individuals with EC. The expressing level of HSF1 was positively related to infiltration of M2 macrophages (P < 0.05). The expression of HSF1 in macrophages was an independent factor for DFS (P = 0.002) and OS (P = 0.002) in ESCC cases. HSF1 was up-regulated in IL-4 stimulation THP1 cells in a time-dependent manner. Under the heat stimulation condition, THP1-derived macrophages were more sensitive than tumor cells. Compared to IL-4 induced-THP1 cells control, the HSF1 knockdown in THP1 cell inhibited the growth and proliferation of ESCC cells. The up-regulation of HSF1 was more rapid and could affect the proliferation of tumor cells in IL4-induced macrophages. The expression of HSF1 in TAMs can also serve as a marker for ESCC prognosis.

H3K27 acetylation activated long noncoding RNA RP11-162G10.5 promotes breast cancer progression via the YBX1/GLO1 axis.

Long noncoding RNAs (lncRNAs) orchestrate critical roles in human tumorigenesis. However, the regulatory mechanism of lncRNAs in tissue-specific expressions in breast cancer (BC) remains poorly understood. This study aims to investigate lncRNA role and mechanisms in BC. RNA sequencing was used to explore differentially expressed lncRNAs in BC and adjacent tissues. H3K27 acetylation (H3K27ac) chromatin immune-precipitation sequencing (ChIP-seq) data of BC cells from the GEO dataset (GSE85158) was retrieved to identify the H3K27ac activated lncRNAs that were involved in tumorigenesis. RP11-162G10.5 was selected as the target lncRNA for further functional and mechanism study. In this study, we identified a novel lncRNA RP11-162G10.5, whose overexpression was specifically driven by H3K27ac in luminal breast cancer. And increased RP11-162G10.5 in BC is correlated with poor patient outcomes. RP11-162G10.5 promotes tumor cell proliferation in vitro and in vivo. Mechanistically, RP11-162G10.5 recruits transcriptional factor YBX1 to the GLO1 promoter, consequently activating GLO1 transcription to modulate the progression of BC. Our findings suggest that the histone modification-activated lncRNA contributes to the oncogenesis of BC. Also, our data reveal a role for RP11-162G10.5 in BC tumorigenesis and may supply a strategy for targeting the RP11-162G10.5 as a potential biomarker and a therapeutic target for breast cancerpatients.

No NETs no TIME: Crosstalk between neutrophil extracellular traps and the tumor immune microenvironment.

The tumor immune microenvironment (TIME) controls tumorigenesis. Neutrophils are important components of TIME and control tumor progression and therapy resistance. Neutrophil extracellular traps (NETs) ejected by activated neutrophils are net-like structures composed of decondensed extracellular chromatin filaments decorated with a plethora of granules as well as cytoplasmic proteins. Many of these harbour post translational modifications. Cancer cells reportedly trigger NET formation, and conversely, NETs alter the TIME and promote tumor cell proliferation and migration. The specific interactions between NETs and TIME and the respective effects on tumor progression are still elusive. In certain tumors, a CD4+ T helper (Th) 2 cell-associated TIME induces NETs and exerts immunosuppressive functions via programmed death 1 (PD-1)/PD-L1, both associated with poorer prognosis. In other cases, NETs induce the proliferation of Th1 cells, associated with an improved prognosis in cancer. In addition, NETs can drive macrophage polarization and often rely on macrophages to promote cancer cell invasion and metastasis. In turn, macrophages can swiftly clear NETs in an immunologically silent manner. The aim of this review is to summarize the knowledge about the mutual interaction between NETs and TIME and its impact on tumor growth and therapy.

Frizzled receptors in melanomagenesis: From molecular interactions to target identification.

Frizzled (FZD) proteins are receptors for the WNT family ligands. Inherited human diseases and genetic experiments using knockout mice have revealed a central role of FZDs in multiple aspects of embryonic development and tissue homeostasis. Misregulated FZD signaling has also been found in many cancers. Recent studies on three out of the ten mammalian FZDs in melanoma have shown that they promote tumor cell proliferation and invasion, via the activation of the canonical WNT/β-catenin or non-canonical PCP signaling pathway. In this concise review, we summarize our current knowledge of individual FZDs in melanoma, discuss the involvement of both the canonical and non-canonical pathways, and describe ongoing efforts to target the FZD receptors for melanoma treatment.

High CD14 Antigen Expression in Urothelial Bladder Carcinoma Establishes that the Inflammatory Microenvironment Promotes Tumour Cell Proliferation

Introduction: CD-14 is an antigen found on the bladder cancer cells that mediated cancer development by providing a supportive inflammatory microenvironment. The study investigates the association of CD14 antigen expression in bladder cancer cells with demographic factors, clinicopathological parameters and recurrent cases by immunohistochemical (IHC) method. Methods: A retrospective study using 59 formalin-fixed paraffin-embedded tissue of urothelial bladder carcinoma cases were subjected to CD14 IHC staining. Results: Most patients were ≥ 65 years old (57.6%), Malay in ethnicity (55.9%) and male predominant (94.9%). CD14 was positively expressed in more than 50% of tumour cells in all grades and stages with the largest percentage seen in the highest grade (Grade III) and stage (Stage IV) of urothelial bladder carcinoma. There was a significant association between CD14 expression and tumour grade of urothelial bladder carcinoma (p = 0.043). However, there was no significant association between CD14 expression with demographic factors, tumour stage or recurrent cases. Conclusion: High CD14 antigen expression by cancer cells establishes that the inflammatory microenvironment promotes tumour cell growth and may suggest CD14 antigen as a poor prognostic marker in urothelial bladder carcinoma.

Advances in the relationship between lung cancer and microbiota

Interaction exists in lung cancer and microbiota. Lung microecological homeostasis can improve the immune tolerance, enhance immune suppression, and inhibit inflammatory responses, to reduce the lung cancer; while lung cancer can lead to pulmonary microecological imbalance, change the lung environment, and promote tumor cell proliferation. Therefore, modulating microbial flora and microecological immunotherapy may be a potential and preventive treatment for lung cancer, to restore tumor immunosuppression and improve patient survival. However, the individual differences in the lung microecology, because of different genetics, ethnic characteristics, and dietary habits, increasing the difficulty of precise diagnosis and treatment, which is also the current bottleneck in the application of microecological immunotherapy. Otherwise, the effectiveness of regulatory measures such as probiotics, prebiotics or antimicrobials is questionable. The research on microbial flora is still in its infancy, and further exploration is needed to form a standardized, effective, and precise treatment plan. So, standardized, effective, and precise microbial flora treatment strategies need to be further explored.

TG2 as a novel breast cancer prognostic marker promotes cell proliferation and glycolysis by activating the MEK/ERK/LDH pathway

BackgroundBreast cancer (BC) is the most common malignant tumor among women worldwide. Tissue transglutaminase 2 (TG2) has been reported as a major player across several types of cancer. However, the effects of TG2 in breast cancer are less known.MethodsThe expression of TG2 in patients with BC was detected by immunochemistry staining and RT-qPCR. The correlation of TG2 expression and clinicopathological factors or overall survival (OS) was analyzed by Chi-square test, Kaplan-Meier, and Cox-regression analysis. The effects of TG2 on cell proliferation and glycolysis were investigated in vivo and in vitro by gain- and loss-of-function experiments.ResultBoth mRNA and protein levels of TG2 were overexpressed in BC tissues and cultured cells. Clinical stage (p = 0.011), molecular subtype (p<0.001) and survival status (p<0.001) were significantly correlated with TG2 expression. Specifically, TG2 expression was positively associated with the clinical stage (r = 0.193, p = 0.005) and OS (r = 0.230, p = 0.001), while negatively associated with molecular subtype (r = − 0.161, p = 0.020). Overexpressed TG2 was a prognostic factor of poor OS by Cox-regression analysis. Gain- and loss-of-function experiments indicated that cell proliferation and glycolysis were regulated by TG2 via the MEK/ERK/LDH pathway. TG2-induced activation of the MEK/ERK/LDH pathway and glycolysis were attenuated by MEK inhibitor U0126.ConclusionTG2 is overexpressed in BC, which can serve as an independent prognostic factor for OS. TG2 promotes tumor cell proliferation and increases glycolysis associated with the activation of the MEK/ERK/LHD pathway.

LRP1B suppresses HCC progression through the NCSTN/PI3K/AKT signaling axis and affects doxorubicin resistance

Accumulating evidence supports the association of somatic mutations with tumor occurrence and development. We aimed to identify somatic mutations with important implications in hepatocellular carcinoma (HCC) and explore their possible mechanisms. The gene mutation profiles of HCC patients were assessed, and the tumor mutation burden was calculated. Gene mutations closely associated with tumor mutation burden and patient overall survival were identified. In vivo and in vitro experiments were performed to verify the effects of putative genes on proliferation, invasion, drug resistance, and other malignant biological behaviors of tumor cells. Fourteen genes with a high mutation frequency were identified. The mutation status of 12 of these genes was closely related to the mutation burden. Among these 12 genes, LRP1B mutation was closely associated with patient prognosis. Nine genes were associated with immune cell infiltration. The results of in vivo and in vitro experiments showed that the knockdown of LRP1B promotes tumor cell proliferation and migration and enhances the resistance of tumor cells to liposomal doxorubicin. LRP1B could directly bind to NCSTN and affect its protein expression level, thereby regulating the PI3K/AKT pathway. Our mutational analysis revealed complex and orchestrated liposomal alterations linked to doxorubicin resistance that may also render cancers less susceptible to immunotherapy and also provides new treatment alternatives.

MicroRNA-206 in human cancer: Mechanistic and clinical perspectives

MicroRNAs (miRNAs), small non-coding RNAs approximately 20–25 nt in length, play important roles via directly binding to the corresponding 3′ UTR of target mRNAs. Recent research has shown that miRNAs cover a wide range of diseases, including several types of cancer. It is interesting to note that miR-206 operates as a tumor suppressor and is downregulated in abundant cancer types, such as breast cancer, lung cancer, colorectal cancer, and so forth. Interestingly, a growing number of studies have also reported that miR-206 could function as an oncogene and promote tumor cell proliferation. Thereby, miR-206 may act as either oncogenes or tumor suppressors under certain conditions. In addition, it was widely acknowledged that restoring tumor-suppressor miR-206 has emerged as an unconventional cancer therapy strategy. Therefore, miR-206 might be a newfangled procedure for achieving a more significant treatment outcome for cancer patients. This review summarizes the role of miR-206 in several cancer types and the contributions made between miR-206 and the diagnosis, treatment, and drug resistance of solid tumors.