Progression Of Human Cancers Research Articles

NCAPD3 is a prognostic biomarker and is correlated with immune infiltrates in glioma.

Non-SMC Condensin II Complex Subunit D3 (NCAPD3) has been linked with the genesis and progression of multiple human cancers. Nevertheless, the scientific value and molecular process of NCAPD3 in glioma remain unclear. We explored the level of NCAPD3 expression in pan-cancer by multiple online databases. And we focused on the level and prognostic value of NCAPD3 expression in glioma by immunohistochemistry (IHC) and survival analysis. Meanwhile, we verified the relationship between NCAPD3, biological function and immune infiltration in glioma by Linkedomics and SangerBox databases. The expression of NCAPD3 was increased in a variety of cancers, including glioma. Its high expression was strongly related to WHO grade (P=0.002) and programmed cell death ligand 1 (PD-L1) expression of glioma (P=0.001). Patients with a high level of NCAPD3 expression had a lower overall survival (OS) in glioma than patients with a low level of NCAPD3 expression. Multivariate statistical analyses showed NCAPD3 expression (P=0.040), WHO grade (P<0.001), 1p/19q codeletion (P<0.001), recurrence (P<0.001), age (P=0.023), and chemotherapy status (P=0.001) were meaningful independent prognostic factors in patients with glioma. Furthermore, bioinformatics analysis proved that NCAPD3 has been linked to immune infiltration in glioma. High level of NCAPD3 expression may serve as a promising prognostic biomarker and correlate with dendritic cell infiltration, representing a potential immunotherapy target in glioma.

SPAG6 overexpression decreases the pro-apoptotic effect of daunorubicin in acute myeloid leukemia cells through the ROS/JNK MAPK axis in a GSTP1-dependent manner

IntroductionAs a malignant hematological disease, the incidence of acute myeloid leukemia (AML) has exhibited an upward trend in recent years. Nevertheless, certain limitations persist in the treatment of AML. Sperm-associated antigen 6 (SPAG6) has been implicated in the onset and progression of various human cancers, with its expression levels significantly elevated in AML. Consequently, we undertook a series of experiments to investigate the role and underlying mechanisms of SPAG6 in AML cell lines.MethodsIn the in vitro experiments of this study, DEPs and GO and KEGG enrichment analysis subsequent to SPAG6 down-regulation were detected by TMT. CCK8 was employed to determine cell viability. The levels of apoptosis and ROS were measured by flow cytometry. In the in vivo experiments, a xenografted tumor model was constructed, and the expression of SPAG6 and GSTP1 in tumor tissues was detected by IHC.ResultsUltimately, our findings indicated that over-expression of SPAG6 promoted cell growth and decreased reactive oxygen species (ROS) and malondialdehyde levels. Furthermore, SPAG6 knockdown was found to diminish mitochondrial membrane potential and facilitate cell apoptosis. In vivo, SPAG6 could also promote tumor growth, suggesting that SPAG6 may serve as a pro-tumor factor. In addition, daunorubicin (DNR) may cause oxidative stress and initiate apoptosis, resulting in oxidative damage to AML cells. However, the overexpression of SPAG6 may attenuate the efficacy of DNR. This was due to SPAG6 promoted GSTP1 expression, thereby reducing ROS levels. Simultaneously, the elevation of GSTP1 and JNK complex may reduce the expression of p-JNK and inhibit the activation of JNK pathway, which might inhibit cell apoptosis.DiscussionIn conclusion, our experiments suggested that upregulated SPAG6 might mitigate the pro-apoptotic effects of DNR through ROS/JNK MAPK axis in a GSTP1-dependent manner.

Autophagy is required for mammary tumor recurrence by promoting dormant tumor cell survival following therapy

BackgroundMortality from breast cancer is principally due to tumor recurrence. Recurrent breast cancers arise from the pool of residual tumor cells, termed minimal residual disease, that survive treatment and may exist in a dormant state for 20 years or more following treatment of the primary tumor. As recurrent breast cancer is typically incurable, understanding the mechanisms underlying dormant tumor cell survival is a critical priority in breast cancer research. The importance of this goal is further underscored by emerging evidence suggesting that targeting dormant residual tumor cells in early-stage breast cancer patients may be a means to prevent tumor recurrence and its associated mortality. In this regard, the role of autophagy in dormant tumor cell survival and recurrence remains unresolved, with conflicting reports of both pro-survival/recurrence-promoting and pro-death/recurrence-suppressing effects of autophagy inhibition in dormant tumor cells. Resolving this question has important clinical implications.MethodsWe used genetically engineered mouse models that faithfully recapitulate key features of human breast cancer progression, including minimal residual disease, tumor dormancy, and recurrence. We used genetic and pharmacological approaches to inhibit autophagy, including treatment with chloroquine, genetic knockdown of ATG5 or ATG7, or deletion of BECN and determined their effects on dormant tumor cell survival and recurrence.ResultsWe demonstrate that the survival and recurrence of dormant mammary tumor cells following therapy is dependent upon autophagy. We find that autophagy is induced in vivo following HER2 downregulation and remains activated in dormant residual tumor cells. Using genetic and pharmacological approaches we show that inhibiting autophagy by chloroquine administration, ATG5 or ATG7 knockdown, or deletion of a single allele of the tumor suppressor Beclin 1 is sufficient to inhibit mammary tumor recurrence, and that autophagy inhibition results in the death of dormant mammary tumor cells in vivo.ConclusionsOur findings demonstrate a pro-tumorigenic role for autophagy in tumor dormancy and recurrence following therapy, reveal that dormant tumor cells are uniquely reliant upon autophagy for their survival, and indicate that targeting dormant residual tumor cells by inhibiting autophagy impairs tumor recurrence. These studies identify a pharmacological target for a cellular state that is resistant to commonly used anti-neoplastic agents and suggest autophagy inhibition as an approach to reduce dormant minimal residual disease in order to prevent lethal tumor recurrence.

NTRK Gene Expression Analysis in Oral Squamous Cell Carcinoma Mexican Population.

Oral cancer holds the sixth position in malignancies worldwide; 90% correspond to oral squamous cell carcinoma (OSCC). Diverse reports suggest that NTRK genes and their receptors are key oncogenesis regulators to tumor progression in human cancers. Objective: To analyze the NTRK and Trk expression and their association with clinicopathological features of OSCC in Mexican patients' samples. Material and Methods: We analyzed 95 OSCC cases of pan-trk immunoexpression through a software-assisted method. Gene expression was analyzed by RT-qPCR employing the ΔΔCT method. Kruskal-Wallis and Spearman's correlation tests were performed. Results: Our mean age was 62.4 (±16.9) years. A total of 37 cases were tumors in the lateral border of the tongue. Age was significantly associated with the anatomical site. 42% (40 of 95) cases were pan-trk positive. A total of 21 cases showed intense immunoexpression predominantly in poorly differentiated OSCC, with a significant correlation between immunoexpression and age and gender. Gene expression showed that poorly differentiated cases exhibited higher NTRK2 expression, while well-differentiated cases demonstrated NTRK3 significantly higher expression. Conclusions: Our results suggest that NTRK family expression is present in OSCC, with differential expression related to differentiation degree. Additional information about their activation or mutational status could reinforce their potential as a possible primary or adjuvant treatment target.

Dehydroepiandrosterone suppresses human colorectal cancer progression through ER stress-mediated autophagy and apoptosis in a p53-independent manner.

Colorectal cancer (CRC) is one of the primary contributors to cancer-related fatalities, with up to 80% of advanced CRC cases exhibiting mutations in the p53 gene. Unfortunately, the development of new compounds targeting mutant p53 is quite limited. The anticancer effects of Dehydroepiandrosterone (DHEA) on various cancers have been reported. However, the suppressive effect of DHEA on CRC cells harboring wild-type or mutant p53 gene remains controversial. This study emphasized revealing the suppressive mechanism and the effect of DHEA on CRC cell tumorigenesis in the presence of wild-type or mutant p53 gene. We demonstrate that DHEA causes CRC cell death and cell cycle arrest in a dose and time-dependent manner. Notably, DHEA exhibits similar inhibitory effects on CRC cells regardless of the p53 gene status. Further study reveals that DHEA induces endoplasmic reticulum (ER) stress and triggers PERK/eIF2/ATF4/CHOP UPR signaling pathway to activate autophagy followed by apoptosis, which was confirmed by suppression of 4-phenylbutyric acid (an ER stress inhibitor) or knockdown either ATF4 or CHOP. DHEA-induced apoptosis was attenuated by silencing ATG5 gene in either p53+/+ or p53-/- CRC cells, indicating autophagy regulation of apoptosis. Furthermore, DHEA treatment accompanied by bafilomycin A1 (a blocker of autophagosome degradation) leads to the accumulation of ATF4, CHOP, DR5, and p21 levels in CRC cells, implying that the degradative autophagy machinery regulates these four molecules. Consistently, DHEA demonstrates its inhibitory effect by suppressing CRC tumor formation in vivo. Altogether, we provide compelling evidence that DHEA is a potential therapeutic candidate for CRC patient treatment regardless of the p53 status through ER stress-PERK-autophagy-apoptosis axis.

Ang-1 promotes tumorigenesis and mediates the anti-cancer effects of Artesunate on Choroidal melanoma via the regulation of Akt/mTOR signaling pathway

The impact of Ang-1 on tumors remains a subject of contention, with its mechanism of action exhibiting complexity in the progression of diverse tumor types. Ang-1 has been shown to promote the progression of glioma, glioma, esophageal and human cervical cancer, whereas it exerts inhibitory effects on the growth of breast and colon cancer. However, the specific function of Ang-1 in CM has not been clarified. This research aims to explore the function of Ang-1 on CM and the underlying mechanism. WB and qPCR were utilized to measure the expression levels of different factors in CM cells. Clonogenic, CCK-8 and Transwell migration assay were used to probe CM cells’ proliferation and migration ability. Xenograft tumor model was used to testify the effect of Ang-1 and Artesunate (ART) on the growth of CM in vivo. We found Ang-1 promoted CM proliferation and migration, while it was inhibited by ART in vitro. Moreover, both ART treatment and Ang-1 knockdown had the effect of suppressing tumor growth in CM xenograft model. Mechanically, Ang-1 activated Akt/mTOR pathway and induced epithelial-mesenchymal transition (EMT) in CM cells. Furthermore, ART regulated Akt/mTOR pathway by decreasing the expression of Ang-1 in CM cells. Ang-1 promotes tumorigenesis of CM by regulating Akt/mTOR pathway, which can be inhibited by ART.

Decorin, an exercise-induced secretory protein, is associated with improved prognosis in breast cancer patients but does not mediate anti-tumorigenic tissue crosstalk in mice

BackgroundRegular exercise can reduce incidence and progression of breast cancer, but the mechanisms for such effects are not fully understood. MethodsWe used a variety of rodent and human experimental model systems to determine whether exercise training can reduce tumor burden in breast cancer and to identify mechanism associated with any exercise training effects on tumor burden. ResultsWe show that voluntary wheel running slows tumor development in the mammary specific polyomavirus middle T antigen overexpression (MMTV-PyMT) mouse model of breast cancer but only when mice are not housed alone. We identify the proteoglycan decorin as a contraction-induced secretory factor that systemically increases in patients with breast cancer immediately following exercise. Moreover, high expression of decorin in tumors is associated with improved prognosis in patients, while treatment of breast cancer cells in vitro with decorin reduces cell proliferation. Notwithstanding, when we overexpressed decorin in murine muscle or injected recombinant decorin systemically into mouse models of breast cancer, elevated plasma decorin concentrations did not result in higher tumor decorin levels and tumor burden was not improved. ConclusionExercise training is anti-tumorigenic in a mouse model of luminal breast cancer, but the effect is abrogated by social isolation. The proteoglycan decorin is an exercise-induced secretory protein, and tumor decorin levels are positively associated with improved prognosis in patients. The hypothesis that elevated plasma decorin is a mechanism by which exercise training improves breast cancer progression in humans is not, however, supported by our pre-clinical data since elevated circulating decorin did not increase tumor decorin levels in these models.

Role of Receptor for Advanced Glycation End-Products in Endometrial Cancer: A Review.

Endometrial cancer (EC) is the most common gynecological malignancy. EC is associated with metabolic disorders that may promote non-enzymatic glycation and activate the receptor for advanced glycation end-products (RAGE) signaling pathways. Thus, we assumed that RAGE and its ligands may contribute to EC. Of particular interest is the interaction between diaphanous-related formin 1 (Diaph1) and RAGE during the progression of human cancers. Diaph1 is engaged in the proper organization of actin cytoskeletal dynamics, which is crucial in cancer invasion, metastasis, angiogenesis, and axonogenesis. However, the detailed molecular role of RAGE in EC remains uncertain. In this review, we discuss epigenetic factors that may play a key role in the RAGE-dependent endometrial pathology. We propose that DNA methylation may regulate the activity of the RAGE pathway in the uterus. The accumulation of negative external factors, such as hyperglycemia, inflammation, and oxidative stress, may interfere with the DNA methylation process. Therefore, further research should take into account the role of epigenetic mechanisms in EC progression.

Abstract B042: Dissection of the T cell infiltrate in mouse pancreatic tumors reveals a diverse tumor-reactive T cell repertoire targeting neoantigens and tumor-associated antigens

Abstract Although pancreatic cancer is generally refractory to immune checkpoint blockade (ICB), recent studies of tumor-infiltrating T cells in human tumor samples demonstrated the presence of in vivo expanded, tumor-reactive T cell receptor (TCR) clonotypes. Here, we explored the T cell repertoire in ICB-refractory murine pancreatic cancer models by combining single-cell transcriptomics with functional TCR characterization. Our initial studies in an orthotopic, transplantable model revealed a remarkable diversity of tumor-reactive TCR clonotypes that could be distinguished from bystander T cells based on gene expression signatures. We identified TCRs exclusively reactive against the tumor of origin, TCRs that also react against an independently derived pancreatic tumor line, and TCRs broadly reactive to tumor cells of diverse tissue origin (e.g. MC38), the latter category being predominant. Subsequent studies were performed in an autochthonous mouse model, in which single focal tumors were induced in the pancreas by means of in vivo electroporation of gene constructs encoding mutant Kras and inducing CRISPR/Cas9-mediated inactivation of tumor suppressor genes. We analyzed the T cell repertoire in tumors with different levels of mutational burden by also inactivating DNA damage repair genes. Interestingly, even in mismatch repair-deficient tumors that featured a high mutational load, the anti-tumor T cell response was primarily directed against recurrent tumor-associated antigens (TAAs) rather than ‘private’ mutanome-encoded neoantigens. Several TAA-reactive TCRs also mediated reactivity against non-transformed cells. Immunopeptidome analysis thus far revealed the identity of 5 cognate antigens targeted by the tumor-reactive TCR repertoire: a mutanome-encoded neoantigen, an epitope encoded by an ectopically expressed endogenous retroviral provirus, and three epitopes derived from TAAs: Lon Peptidase 2 (LONP2), ATPase Na+/K+ Transporting Subunit Beta 3 (ATP1B3) and SEC24B, a component of secretory vesicles. Notably, the overexpression of LONP2 and ATP1B3 was found associated with progression of human cancers, whereas silencing was shown to suppress tumor cell growth. Overexpression of SEC24B in cancers has not been reported, but this protein plays an essential role in the secretory pathway of acinar cells. In summary, in-depth analysis of the natural T cell response in murine pancreatic cancer models revealed a diverse tumor-reactive T cell repertoire that is predominantly directed against TAAs, some of which are also expressed in normal somatic cells. These findings underline the importance of uncovering the antigen-specificity of the natural tumor-reactive TCR repertoire, both in mouse models and human tumor samples, to assess its therapeutic potential and safety with regard to personalized immunotherapy. Citation Format: Stefan Zens, Hannes Kehm, Daniel Baumann, Aline Konrad, Zibo Meng, Arnoud H. de Ru, Julian Mochayedi, Francesca Lucato, Angelika B. Riemer, Isabel Poschke, Michael Volkmar, Peter A. van Veelen, Rienk Offringa. Dissection of the T cell infiltrate in mouse pancreatic tumors reveals a diverse tumor-reactive T cell repertoire targeting neoantigens and tumor-associated antigens [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B042.

Mitochondrial complex I promotes kidney cancer metastasis.

Most kidney cancers are metabolically dysfunctional1-4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-13C]acetate and [U-13C]glutamine infusionsin patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that ofprimary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site.

Environmentally relevant concentration PFNA promotes degradation of SMAD7 to drive progression of ovarian cancer via TGF-β/SMADs signaling pathway

Perfluorononanoic acid (PFNA), an acknowledged environmental endocrine disruptor, is increasingly utilized as a substitute for perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Despite its growing use, limited research has been conducted to investigate its potential impact on tumorigenesis and progression, and the potential molecular mechanisms. Earlier studies linked perfluoroalkyl and polyfluoroalkyl substances (PFAS) exposure to breast and gynecological cancer progression in humans, lacking a clear understanding of the underlying mechanisms, notably in ovarian cancer. Our investigation into PFNA's effects at environmental concentrations (0.25–2 mM) showed no significant impact on cell proliferation but a notable increase in invasion and migration of ovarian cancer cells. This led to alterations in epithelial-mesenchymal transition (EMT) markers, including Claudin1, Vimentin, and Snail. Notably, PFNA exposure activated the TGF-β/SMADs signaling pathway. Crucially, SMAD7 degradation through the ubiquitin-proteasome system emerged as PFNA's pivotal molecular target for inducing EMT, corroborated in mouse models. In summary, this study presented evidence that environmentally relevant concentrations of PFNA could induce SMAD7 degradation via the proteasome pathway, subsequently activating the TGF-β/SMADs signaling pathway, and promoting EMT in ovarian cancer. These results illuminated the association between PFNA exposure and metastasis of ovarian cancer.

S-acylation of Ca2+ transport proteins in cancer.

Alterations in cellular calcium (Ca2+) signals have been causally associated with the development and progression of human cancers. Cellular Ca2+ signals are generated by channels, pumps, and exchangers that move Ca2+ ions across membranes and are decoded by effector proteins in the cytosol or in organelles. S-acylation, the reversible addition of 16-carbon fatty acids to proteins, modulates the activity of Ca2+ transporters by altering their affinity for lipids, and enzymes mediating this reversible post-translational modification have also been linked to several types of cancers. Here, we compile studies reporting an association between Ca2+ transporters or S-acylation enzymes with specific cancers, as well as studies reporting or predicting the S-acylation of Ca2+ transporters. We then discuss the potential role of S-acylation in the oncogenic potential of a subset of Ca2+ transport proteins involved in cancer.

A Phenotypic Approach to the Discovery of Potent G-Quadruplex Targeted Drugs.

G-quadruplex (G4) sequences, which can fold into higher-order G4 structures, are abundant in the human genome and are over-represented in the promoter regions of many genes involved in human cancer initiation, progression, and metastasis. They are plausible targets for G4-binding small molecules, which would, in the case of promoter G4s, result in the transcriptional downregulation of these genes. However, structural information is currently available on only a very small number of G4s and their ligand complexes. This limitation, coupled with the currently restricted information on the G4-containing genes involved in most complex human cancers, has led to the development of a phenotypic-led approach to G4 ligand drug discovery. This approach was illustrated by the discovery of several generations of tri- and tetra-substituted naphthalene diimide (ND) ligands that were found to show potent growth inhibition in pancreatic cancer cell lines and are active in in vivo models for this hard-to-treat disease. The cycles of discovery have culminated in a highly potent tetra-substituted ND derivative, QN-302, which is currently being evaluated in a Phase 1 clinical trial. The major genes whose expression has been down-regulated by QN-302 are presented here: all contain G4 propensity and have been found to be up-regulated in human pancreatic cancer. Some of these genes are also upregulated in other human cancers, supporting the hypothesis that QN-302 is a pan-G4 drug of potential utility beyond pancreatic cancer.

Cortactin: A major cellular target of viral, protozoal, and fungal pathogens.

Many viral, protozoal, and fungal pathogens represent major human and animal health problems due to their great potential of causing infectious diseases. Research on these pathogens has contributed substantially to our current understanding of both microbial virulence determinants and host key factors during infection. Countless studies have also shed light on the molecular mechanisms of host-pathogen interactions that are employed by these microbes. For example, actin cytoskeletal dynamics play critical roles in effective adhesion, host cell entry, and intracellular movements of intruding pathogens. Cortactin is an eminent host cell protein that stimulates actin polymerization and signal transduction, and recently emerged as fundamental player during host-pathogen crosstalk. Here we review the important role of cortactin as major target for various prominent viral, protozoal and fungal pathogens in humans, and its role in human disease development and cancer progression. Most if not all of these important classes of pathogens have been reported to hijack cortactin during infection through mediating up- or downregulation of cortactin mRNA and protein expression as well as signaling. In particular, pathogen-induced changes in tyrosine and serine phosphorylation status of cortactin at its major phospho-sites (Y-421, Y-470, Y-486, S-113, S-298, S-405, and S-418) are addressed. As has been reported for various Gram-negative and Gram-positive bacteria, many pathogenic viruses, protozoa, and fungi also control these regulatory phospho-sites, for example, by activating kinases such as Src, PAK, ERK1/2, and PKD, which are known to phosphorylate cortactin. In addition, the recruitment of cortactin and its interaction partners, like the Arp2/3 complex and F-actin, to the contact sites between pathogens and host cells is highlighted, as this plays an important role in the infection process and internalization of several pathogens. However, there are also other ways in which the pathogens can exploit the function of cortactin for their needs, as the cortactin-mediated regulation of cellular processes is complex and involves numerous different interaction partners. Here, the current state of knowledge is summarized.

LncRNA HOXA‑AS2 promotes the progression of epithelial ovarian cancer via the regulation of miR‑372.

Long non-coding RNAs, such as homeobox A cluster antisense RNA2 (HOXA-AS2) are understood to be involved in tumor growth and development of numerous cancers. However, the role of HOXA-AS2 in the progression of human epithelial ovarian cancer (EOC) remains unclear. In the present study, the expression of HOXA-AS2 was found to be upregulated in EOC tissues compared with noncancerous tissues, and to be strongly correlated to an advanced Federation International of Gynecology and Obstetrics grade and poor prognosis. Knockdown of HOXA-AS2 in the EOC cells inhibited cell proliferation, invasion and migration, as well as inducing cell apoptosis. The ENCORI database was used to screen the microRNAs (miRNAs/miRs) that bound to HOXA-AS2, and one was tested using RNA pull-down and luciferase reporter assays. It was demonstrated that HOXA-AS2 functioned through the competing endogenous RNA mechanism to regulate miR-372. It was also demonstrated that the downregulation of miR-372 reversed the inhibitory effects of the knockdown of HOXA-AS2 in EOC cells. These results indicated that HOXA-AS2 promoted EOC progression by regulating the miR-372, which suggests that HOXA-AS2 may be a therapy target for EOC.

Human gastric cancer progression and stabilization of ATG2B through RNF5 binding facilitated by autophagy-associated CircDHX8

The role of circDHX8 in the interplay between autophagy and gastric cancer (GC) progression remains unclear. In this study, we investigated the mechanism underlying the role of hsa_circ_003899 (circDHX8) in the malignancy of GC. Differential expression of circRNAs between GC and normal tissues was determined using circle-seq and microarray datasets (GSE83521). These circRNAs were validated using qPCR and Sanger sequencing. The function of circDHX8 was investigated through interference with circDHX8 expression experiments using in vitro and in vivo functional assays. Western blotting, immunofluorescence, and transmission electron microscopy were used to establish whether circDHX8 promoted autophagy in GC cells. To elucidate the mechanism underlying the circDHX8-mediated regulation of autophagy, we performed bioinformatics analysis, RNA pull-down, mass spectrometry (MS), RNA immunoprecipitation (RIP), and other western Blot related experiments. Hsa_circ_0003899 (circDHX8) was identified as upregulated and shown to enhance the malignant progression in GC cells by promoting cellular autophagy. Mechanistically, circDHX8 increased ATG2B protein levels by preventing ubiquitin-mediated degradation, thereby facilitating cell proliferation and invasion in GC. Additionally, circDHX8 directly interacts with the E3 ubiquitin-protein ligase RNF5, inhibiting the RNF5-mediated degradation of ATG2B. Concurrently, ATG2B, an acetylated protein, is subjected to SIRT1-mediated deacetylation, enhancing its binding to RNF5. Consequently, we established a novel mechanism for the role of circDHX8 in the malignant progression of GC.

Targeting SHP2 Cryptic Allosteric Sites for Effective Cancer Therapy.

SHP2, a pivotal component downstream of both receptor and non-receptor tyrosine kinases, has been underscored in the progression of various human cancers and neurodevelopmental disorders. Allosteric inhibitors have been proposed to regulate its autoinhibition. However, oncogenic mutations, such as E76K, convert SHP2 into its open state, wherein the catalytic cleft becomes fully exposed to its ligands. This study elucidates the dynamic properties of SHP2 structures across different states, with a focus on the effects of oncogenic mutation on two known binding sites of allosteric inhibitors. Through extensive modeling and simulations, we further identified an alternative allosteric binding pocket in solution structures. Additional analysis provides insights into the dynamics and stability of the potential site. In addition, multi-tier screening was deployed to identify potential binders targeting the potential site. Our efforts to identify a new allosteric site contribute to community-wide initiatives developing therapies using multiple allosteric inhibitors to target distinct pockets on SHP2, in the hope of potentially inhibiting or slowing tumor growth associated with SHP2.

Effects of metformin on cancers in experimental and clinical studies: Focusing on autophagy and AMPK/mTOR signaling pathways.

Metformin (MET) is a preferred drug for the treatment of type 2 diabetes mellitus. Recent studies show that apart from its blood glucose-lowering effects, it also inhibits the development of various tumours, by inducing autophagy. Various studies have confirmed the inhibitory effects of MET on cancer cell lines' propagation, migration, and invasion. The objective of the study was to comprehensively review the potential of MET as an anticancer agent, particularly focusing on its ability to induce autophagy and inhibit the development and progression of various tumors. The study aimed to explore the inhibitory effects of MET on cancer cell proliferation, migration, and invasion, and its impact on key signaling pathways such as adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and PI3K. This review noted that MET exerts its anticancer effects by regulating key signalling pathways such as phosphoinositide 3-kinase (PI3K), LC3-I and LC3-II, Beclin-1, p53, and the autophagy-related gene (ATG), inhibiting the mTOR protein, downregulating the expression of p62/SQSTM1, and blockage of the cell cycle at the G0/G1. Moreover, MET can stimulate autophagy through pathways associated with the 5' AMPK, thereby inhibiting he development and progression of various human cancers, including hepatocellular carcinoma, prostate cancer, pancreatic cancer, osteosarcoma, myeloma, and non-small cell lung cancer. In summary, this detailed review provides a framework for further investigations that may appraise the autophagy-induced anticancer potential of MET and its repurposing for cancer treatment.

The novel prognostic marker SPOCK2 regulates tumour progression in melanoma.

Secreted protein acidic and cysteine rich/osteonectin, cwcv and kazal-like domain proteoglycan 2 (SPOCK2) is a protein that regulates cell differentiation and growth. Recent studies have reported that SPOCK2 plays important roles in the progression of various human cancers; however, the role of SPOCK2 in melanoma remains unknown. Therefore, this study investigated the roles of SPOCK2 and the related mechanisms in melanoma progression. To evaluate the clinical significance of SPOCK2 expression in patients with melanoma, we analysed the association between SPOCK2 expression and its prognostic value for patients with melanoma using systematic multiomic analysis. Subsequently, to investigate the roles of Spock2 in melanoma progression invitro and invivo, we knocked down Spock2 in the B16F10 melanoma cell line. High SPOCK2 levels were positively associated with good prognosis and long survival rate of patients with melanoma. Spock2 knockdown promoted melanoma cell proliferation by inducing the cell cycle and inhibiting apoptosis. Moreover, Spock2 downregulation significantly increased cell migration and invasion by upregulating MMP2 and MT1-MMP. The increased cell proliferation and migration were inhibited by MAPK inhibitor, and ERK phosphorylation was considerably enhanced in Spock2 knockdown cells. Therefore, Spock2 could function as a tumour suppressor gene to regulate melanoma progression by regulating the MAPK/ERK signalling pathway. Additionally, Spock2 knockdown cell injection induced considerable tumour growth and lung metastasis in C57BL6 mice compared to that in the control group. Our findings suggest that SPOCK2 plays crucial roles in malignant progression of melanoma and functions as a novel therapeutic target of melanoma.

Anticancer Properties of Different Varieties of Date Palm (Phoenix dactylifera L.) Leaf Extracts in Human Tumor Cells: a Comparative Study.

Plant polyphenols are nutraceutical components with relevant biological effects on human health. They act against development of several diseases including cancer. In this study, the methanolic extracts of four date palm Phoenix dactylifera leaves (Deglet Noor (DN), Barhee (B), Khalas (KS) and Khunezi (KZ)) collected from south Tunisia were preliminary analyzed for their effects against U87 (human glioblastoma) and MDA-MB-231 (human breast cancer) cell line development. Results showed that Barhee extract (30μg/mL) was the most efficient to reduce the growth of both tumor cells to about 40% (p < 0.05) without inducing cytotoxicity. Significantly, KS, KZ, DN and B extracts (30μg/mL) decreased MDA-MB-231 and U87 cell adhesion towards fibrinogen and fibronectin. Using integrin blocking antibodies, leaf extracts competitively decreased human glioblastoma cell attachment to immobilized antibodies by interfering to αvβ3 and α5β1 integrin receptors. At the same concentration, extracts decreased MDA-MB-23 and U87 cell migration performed with wound healing assay. Particularly, Barhee and Deglet Noor leaf extracts (30μg/mL) significantly reduced U87 cell invasion by 52.92% (p < 0.01) and 74.56% (p < 0.01), respectively. Collegially, our findings revealed beneficial proprieties of four varieties of date palm leaf especially those displayed by DN and B extracts that may serve as active candidates against human glioblastoma and breast cancer progression.