P53 Tumor Suppressor Gene Research Articles

Apoptotic Potential of Glucomoringin Isothiocyanate (GMG-ITC) Isolated from Moringa oleifera Lam Seeds on Human Prostate Cancer Cells (PC-3).

Inhibition of several protein pathways involved in cancer cell regulation is a necessary key in the discovery of cancer chemotherapy. Moringa oleifera Lam is often used in traditional medicine for the treatment of various illnesses. The plant contains glucomoringin isothiocyanate (GMG-ITC) with therapeutic potential against various cancer cells. Therefore, GMG-ITC was evaluated for its cytotoxicity against the PC-3 prostate cancer cell line and its potential to induce apoptosis. GMG-ITC inhibited cell proliferation in the PC-3 cell line with IC50 value 3.5 µg/mL. Morphological changes as a result of GMG-ITC-induced apoptosis showed chromatin condensation, nuclear fragmentation, and membrane blebbing. Additionally, Annexin V assay showed proportion of cells in early and late apoptosis upon exposure to GMG-ITC in a time-dependent manner. Moreover, GMG-ITC induced a time-dependent G2/M phase arrest, with reduction of 39.1% in the PC-3 cell line. GMG-ITC also activates apoptotic genes including caspase, tumor suppressor gene (p53), Akt/MAPK, and Bax of the proapoptotic Bcl family. Early apoptosis proteins (JNK, Bad, Bcl2, and p53) were significantly upregulated upon GMG-ITC treatment. It is concluded that apoptosis induction was observed in PC-3 cells treated with GMG-ITC. These phenomena suggest that GMG-ITC from M. oleifera seeds could be useful as a future cytotoxic agent against prostate cancer.

Suppression of tumor growth and apoptosis induction by pomegranate seed nano-emulsion in mice bearing solid Ehrlich carcinoma cells

Despite the high antioxidant and penetration ability of pomegranate seed oil (PSO), the in vivo antitumor activity of PSO nano-emulsion has not been well investigated. Therefore, this study was undertaken to estimate the antitumor activity and safety of PSO nano-emulsion in mice bearing Ehrlich solid carcinoma cells. For tumor inoculation, about 2 × 106 viable Ehrlich tumor cells (200 µl) were implanted intramuscularly in the left thigh of hind leg. Once a solid tumor appears on the 10th day of transplantation; the mice were randomly divided into five groups (5 animals/group). Characterization of the PSO nano-emulsion using a Zeta sizer Malvern instrument and transmission electron microscope (TEM) revealed that the PSO nano-droplets were well dispersed with an average particle size of 8.95 nm and a spherical shape. Treatment with PSO nano-emulsions caused a significant reduction in the tumor size and weight, in a dose dependent manner, compared to tumor control group. Marked dose dependent elevations in the DNA damage level together with significant increases in the tumor suppressor p53, Bax and Caspase genes and reductions in the anti-apoptotic Bcl2 gene were also observed in the tumor tissue of mice given PSO nano-emulsions. Histological examination also revealed apoptosis and necrosis of tumor cells and tumor infiltration with inflammatory cells after PSO nano-emulsion treatment. However, high DNA damage was noticed in the liver and kidney tissues of mice given the highest dose of PSO nano-emulsion (400 mg/kg). Therefore, we concluded that PSO nano-emulsion exhibited a potent antitumor activity through induction of DNA breaks that triggers apoptosis of tumor cells but the highest dose caused genotoxicity to liver and kidney tissues, thus it is recommended to use doses lower than 400 mg/kg of PSO nano-emulsion as an alternative drugs for chemotherapy.

P53 and Myofibroblast Apoptosis in Organ Fibrosis.

Organ fibrosis represents a dysregulated, maladaptive wound repair response that results in progressive disruption of normal tissue architecture leading to detrimental deterioration in physiological function, and significant morbidity/mortality. Fibrosis is thought to contribute to nearly 50% of all deaths in the Western world with current treatment modalities effective in slowing disease progression but not effective in restoring organ function or reversing fibrotic changes. When physiological wound repair is complete, myofibroblasts are programmed to undergo cell death and self-clearance, however, in fibrosis there is a characteristic absence of myofibroblast apoptosis. It has been shown that in fibrosis, myofibroblasts adopt an apoptotic-resistant, highly proliferative phenotype leading to persistent myofibroblast activation and perpetuation of the fibrotic disease process. Recently, this pathological adaptation has been linked to dysregulated expression of tumour suppressor gene p53. In this review, we discuss p53 dysregulation and apoptotic failure in myofibroblasts and demonstrate its consistent link to fibrotic disease development in all types of organ fibrosis. An enhanced understanding of the role of p53 dysregulation and myofibroblast apoptosis may aid in future novel therapeutic and/or diagnostic strategies in organ fibrosis.

Anti-Cancer Effect of Dorema Ammoniacum Gum by Targeting Metabolic Reprogramming by Regulating APC, P53, KRAS Gene Expression in HT-29 Human Colon Cancer Cells.

Colorectal cancer is a heterogeneous disease that leads to metabolic disorders due to multiple upstream genetic and molecular changes and interactions. The development of new therapies, especially herbal medicines, has received much global attention. Dorema ammoniacum is a medicinal plant. Its gum is used in healing known ailments. Studying metabolome profiles based on nuclear magnetic resonance 1HNMR as a non-invasive and reproducible tool can identify metabolic changes as a reflection of intracellular fluxes, especially in drug responses. This study aimed to investigate the anti-cancer effects of different gum extracts on metabolic changes and their impact on gene expression in HT-29 cell. Extraction of Dorema ammoniacum gum with hexane, chloroform, and dichloromethane organic solvents was performed. Cell inhibition growth percentage and IC50 were assessed. Following treating the cells with dichloromethane extract, p53, APC, and KRAS gene expression were determined. 1HNMR spectroscopy was conducted. Eventually, systems biology software tools interpreted combined metabolites and genes simultaneously. The lowest determined IC50 concentration was related to dichloromethane solvent, and the highest was hexane and chloroform. The expression of the KRAS oncogene gene decreased significantly after treatment with dichloromethane extract compared to the control group, and the expression of tumor suppressor gene p53 and APC increased significantly. Most gene-altered convergent metabolic phenotypes. This study's results indicate that the dichloromethane solvent of Dorema ammoniacum gum exhibits its antitumor properties by altering the expression of genes involved in HT-29 cells and the consequent change in downstream metabolic reprogramming.

Pathogenetic model of survivin-dependent molecular signalling pathways in tumorigenesis of oral cancer and precursor lesions.

p53 tumour suppressor gene limits unchecked cellular growth in response to DNA damage, by causing G1 arrest and the activation of apoptosis. Inhibitors of apoptosis include survivin which acts by inhibition of caspases. Survivin has a significant role as a cell cycle modulator and is only minimally present in mature tissues. Aberrant expression of p53 and survivin has been evaluated in various carcinomas. Thus, the objective of this research was to elucidate the co-expression of p53 and survivin in tissue samples of Oral Potentially Malignant Disorders (OPMDs) and Oral Squamous Cell Carcinoma (OSCCs). Thirty tissue samples of OPMDs and 30 tissue samples of OSCCs taken from department archives were used in the study. Expression of p53 and survivin was analyzed in the study groups by the help of immunohistochemistry. Also, co-expression of both the markers was evaluated. The expression of p53 and survivin in the oral epithelium of patients with OSCCs was significantly higher than that in patients with OPMDs (P value ≤0.05). Our results provide insights into the altered survivin and p53 co-expression with significant immunoexpression within the study groups. Therefore, survivin and p53 could be better markers for identifying cell proliferation and apoptotic pathway. Also, malignant transformation rate of OPMD increases with increased expression of these markers.

PREVALENCE OF NODAL METASTASIS ASSOCIATED WITH DECREASED EXPRESSION OF CYTOTOXIC CD8+ T LYMPHOCYTE IN P53 COLO-RECTAL CARCINOMA IN SOUTHERN ETHNICS OF TAMIL NADU

Colorectal Cancer (CRC) is one of the most common cancers in the world. The most frequent mutated p53 tumour suppressor gene predisposes resistance to therapy, resulting in poor prognosis in this disease. Our study aimed to evaluate the expression of CD8+lymphocytes in mutant p53 CRCs and to nd out its correlation with other tumour related aggressive parameters like tumour size, site, nodal status etc. This study was conducted at Department of Pathology, Tirunelveli Medical College, Tamil Nadu, India. In this study 51 patients with colorectal cancers were included. Age at diagnosis, gender, tumour site, tumour size, tumour margin, tumour grade, histological type, depth of invasion, tumour budding, vascular and neural invasion were analysed. An Immunohistochemical study was done for the p53 mutation gene, and quantication of Cd8 lymphocytes. Among the 38cases with mutant p53 gene, high CD8 score was seen in 14 cases (37%) and low CD8 score was found in 24(63%) cases. p53 mutant colorectal cancer expressing low CD8 score were signicantly correlated with increased nodal metastasis (p value<0.027) and age ((p value<0.03). This study highlights the signicant correlation of CD8 T-lymphocyte with Age and Nodal metastasis, thus helping to predict the prognosis of colorectal cancers and reduce social stigma caused by this disease

The New Way to Define Key Oncogenic Drivers of Small Cell Lung Cancer

Small-cell lung cancer (SCLC) continues to be the deadliest of all lung cancer types. Its high mortality is largely attributed to the unchangeable development of resistance to standard chemo/radiotherapies, which have remained invariable for the past 30 years, underlining the need for new therapeutic approaches. Recent studies of SCLC genome revealed a large number of somatic alterations and identified remarkable heterogeneity of the frequent mutations except for the loss of both RB and P53 tumor suppressor genes (TSGs). Identifying the somatic alterations scattered throughout the SCLC genome will help to define the underlying mechanism of the disease and pave the way for the discovery of therapeutic vulnerabilities associated with genomic alterations. The new technique made it possible to determine the underlying mechanism for the discovery of therapeutic targets. To these ends, the techniques have been focused on understanding the molecular determinants of SCLC.

Comparative toxicological evaluations of novel forms nano-pesticides in liver and lung of albino rats

Copper oxide Nanoparticles (CuONPs) are used in different agricultural applications. Large amounts of CuONPs cause organ dysfunction in animals. Our study aim to compare between the toxic effects of CuONanSphere (CuONSp) and CuONanoFlower (CuONF) as new nano-pesticides, determine a less toxic form when used in agricultural applications. To characterize CuONSp and CuONF, we used X-ray diffraction (XRD), Field emission scanning electron microscopy (SEM), and High resolution transmission electron microscopy (HRTEM) and Zeta-sizer device.18 adult male albino rats were divided into three groups (n = 6), (I) control group, (II) and (III) groups were given orally 50 mg/kg/day of CuONSp and CuONF 30 days respectively. CuONSp induced oxidant-antioxidant abnormalities, including an increase in malondialdhyde (MDA) and a decrease in glutathione (GSH) in comparison to CuONF-treated one. CuONSp induced an increase in liver enzymes activities compared to CuONF. Tumour necrosis factor-alfa (TNF-α) detected an increased in liver and lung compared to CuONF. However, histological examinations revealed changes in CuONSp group than CuONF group. Changes in immune-expressions of TNF-α, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kβ) and tumour suppressor gene (p53) were also more identified in CuONSp group than CuONF group. Ultrastructural studies of liver and lung tissues marked alternations were observed in CuONSp group than CuONF group. In conclusion, CuONSp induced biological alternation in liver and lung more than CuONF. So, CuONF is less toxic compared to CuONSp when used as nano-pesticide in agricultural applications.Graphical abstract

SCF-FBXL8 contributes to liver metastasis and stem-cell-like features in colorectal cancer cells by mediating ubiquitination and degradation of TP53.

FBXL8 is a conserved F-box protein, belonging to the ubiquitin ligase complex, which promotes the development and progression of tumours. However, the regulation function and mechanism of FBXL8's involvement in colorectal cancer (CRC) remain unclear. RT-PCR is used to detect gene expression levels. Protein levels were determined by western blotting and flow cytometry. The bindings of FBXL8 and p53 and ubiquitination levels were detected by cell transfection and immunoprecipitation. The transwell assay was used to measure the ability of cells to migrate and invade. Animal studies were used to verify the function of FBXL8 in vivo. The expression of FBXL8 was up-regulated in CRC tissues, and its overexpression was associated with poor prognosis in CRC patients. The up-regulation of FBXL8 promoted the proliferation, invasion and migration of CRC tumour cells and maintained the stem-cell characteristics of colorectal tumour cells. Further analysis demonstrated that FBXL8 targeted p53 and reduced its stability through ubiquitination. Knockout of FBXL8 down-regulated the proliferation, migration and stem-like properties of tumour cells. CRC mouse xenograft tumour model confirmed that FBXL8 gene knockout inhibited tumour formation and liver metastasis. FBXL8 was highly expressed in CRC. Mechanism studies have shown that FBXL8 degraded tumour suppressor gene p53 by ubiquitination. FBXL8 knockout inhibited the proliferation and stem characteristics of CRC cells, so SCF-FBXL8-TP53 has potential to be used as a therapeutic target for CRC in subsequent studies.

OBESITY AND LUNG CANCER (INVESTIGATING THE RELATIONSHIP)

Obesity is a global issue, and it leads to various health comorbidities like cardiovascular disease, diabetes type II and certain cancers. The relationship between obesity and cancer, specifically the lung cancer has been studied by many researchers, and they have revealed a positive association of lung cancer with obese individuals, but the mechanism is still not completely understood. Higher BMI which usually falls between 25 to 34.9 kg/m2 is found to reduce the rate of mortality in lung cancer patients. It has been found that in obese individual the p53 tumor suppressor gene is highly upregulated which play a critical role in decreasing the risk of lung cancer. Different studies have suggested that lung cancer has different progression rates depending on smokers and nonsmokers, and the size of the waist including the waist circumference (WC), waist-to-hip ratio (WHR), and the measures of overall obesity in the body, is associated with increased in risk of lung cancer regardless of BMI. This review unveils the major relation between obesity with lung cancer.

The Effect of Pantoprazole on Tumor Growth and Apoptosis in Gastric Cancer Stem-Like Cells

Background: Gastric cancer is a daunting global problem with unsatisfactory treatment. Due to the key role of Gastric Cancer Stem-like Cells (GCSCs) in all stages of gastric cancer and the failure of contemporary anticancer therapies, many research efforts are focusing on these treatmentresistant cells. Pantoprazole, as recently considered antitumor agent with well-documented effects on tumorigenesis inhibition, has seldom been investigated in GCSCs in previous studies. We aimed to study the influence of pantoprazole on cell proliferation, apoptosis, and the transcription of genes involved in the cell proliferation and apoptosis pathways. Materials and Methods: Herein, we isolated GCSCs from MKN-45 cell line, on a non-adherent surface and then evaluated the effect of pantoprazole on cell growth and apoptosis of GCSCs by means of MTT, DNA laddering and quantitative real-time RT-PCR techniques. Results: Our findings showed that treated cells with pantoprazole decreased cell proliferation and induced apoptosis. PCNA (Proliferating Cell Nuclear Antigen) and antiapoptotic Bcl2 genes were downregulated and Bax and CASP3 proapoptotic genes, as well as tumor suppressor p53 gene, were overexpressed. Conclusion: Our results revealed that pantoprazole induced apoptosis and declined tumor growth and support the idea that pantoprazole played as a promising breakthrough in gastric cancer therapy.

Exploring the Bioactive Mycocompounds (Fungal Compounds) of Selected Medicinal Mushrooms and Their Potentials against HPV Infection and Associated Cancer in Humans.

Medicinal mushrooms have been used as a medicinal tool for many centuries and, nowadays, are used in the prevention and therapy of various diseases, including as an adjunct to cancer treatment. It is estimated that 14-16% of global cancer cases are caused by infectious events; one well-known infectious agent that leads to cancer is the human papillomavirus (HPV). HPV is responsible for more than 99.7% of cervical cancer cases and also may play a role in vaginal, vulvar, penile, anal, rectal, and oropharyngeal carcinogenesis. Coriolus versicolor, a basidiomycetes class mushroom, consists of glycoproteins called polysaccharide-K (PSK) and polysaccharopeptide (PSP), which are mainly responsible for its effectiveness in the fight against a variety of cancers. Its beneficial effect lies in its ability to arrest different phases of the cell cycle, immunomodulation or induction of apoptosis. Coriolus versicolor extractcan reduces BCL-2 expression or increases the expression of p53 tumour suppressor genes in breast tumour cell lines. Inhibition of proliferation was also demonstrated with HeLa cells, while cervical cytology abnormalities improved in patients who locally applied Coriolus versicolor-based vaginal gel. Coriolus versicolor extract itself, and also its combination with another medicinal mushroom, Ganoderma lucidum, leads to improved HPV clearance in HPV cervical or oral-positive patients. Medicinal mushrooms can also increase the effectiveness of vaccination. This review considers the use of medicinal mushrooms as a suitable adjunct to the treatment of many cancers or precanceroses, including those caused by the HPV virus.

Curcumin nanocapsules effect in apoptotic processes, gene expression, and cell cycle on Hep-G2 cell lines.

Curcumin has antioxidant and antiproliferative properties, and its therapeutic effect must be considered. Nanocurcumin capsules showed a potential increase against in vitro biological cancer. This study sought to determine how curcumin nanoparticles and nanocapsules affected the expression of p53, Bcl-2, Bax, and Bax in a liver cancer cell line (Hep-G2). Mechanisms of apoptosis were also examined in this cell line. This study used quantitative real-time polymerase chain reaction (qRT-PCR) to analyze the p53, Bcl-2, Bax, and Caspase-3 gene pathways and to evaluate the molecular mechanisms responsible for the efficacy of curcumin nanoparticles (CNPs) and curcumin nanocapsules (CNCs) against liver cell lines. Flow cytometry was used to check for signs of apoptosis and the cell cycle. Curcumin nanocapsules produced by the ball milling process at 90min significantly boosted the populations of apoptotic cells in a dose- and time-dependent manner. The mRNA expression analysis revealed that the proapoptotic Bax, Caspase-3, and the tumor suppressor gene p53 were upregulated throughout the process started by curcumin nanocapsules and decreased in the Bcl-2/Bax ratio. This research provides a fresh understanding of the molecular mechanisms behind the liver cancer-fighting abilities of curcumin nanoparticles. Curcumin nanocapsules produced through a unique mechanical technique can be used as an anticancer agent.

Global and promoter specific hypermethylation of tumor suppressor genes P16, SOCS1, and SHP1 in oral squamous cell carcinoma and oral submucous fibrosis.

Aberrant methylation pattern leads to altered gene expression, that is, involved in the transformation of various cancers, including oral squamous cell carcinoma (OSCC). In the present study, an attempt has been made to examine the association of global and promoter-specific methylation of tumor suppressor genes in patients with OSCC and oral submucous fibrosis (OSMF). Promoter-specific methylation of tumor suppressor genes P16, SOCS1, and SHP1 had been studied earlier for their aberrant methylation patterns in other cancers; however, these studies were mainly conducted in-vitro or in animal models, and as such, only a few studies are available on human samples. In the present study evaluation of promoter-specific methylation of genes P16, SOCS1, and SHP1 in 76 patients' blood and tissue samples was done and compared with methylation of 35 healthy control samples using qPCR. Further, these samples were analyzed for global methylation patterns using ELISA. The results have shown a significant decreasing trend of promoter methylation (OSCC > OSMF > Controls); the methylation indices (MI) were significantly higher in OSCC than in the controls. The median MI of three genes for OSCC were P16MI (0.96), SHP1MI (0.79), and SOCS1 (0.80). Similarly, median MIs for OSMF were P16MI (0.18), SHP1 MI (0.19), and SOCS1 MI (0.5) against controls with MI (0) for each of the three genes. The global methylation %mC values were 1.9, 0.5, and 0.1, respectively. The values of MI and %mC were found to correlate with various risk factors such as tobacco, smoking, and alcohol consumption, which are positively involved in OSMF pathogenesis followed by oral cancer progression. Further, the methylation trend in tissue was reflected in blood samples, proving a window for methylation load to be used as a lesser invasive biomarker. The sensitivity and specificity of methylation load were also found reasonable. Therefore, the current study suggests that there may be a role of global and promoter-specific methylation load in the transition of OSMF to OSCC.

Expression of p53 as Potential Biomarker in Oral Submucous Fibrosis: An Immunohistochemical Study.

Oral submucous fibrosis (OSMF) is potentially malignant disorder known to transform into oral cancer. The malignant transformation is often associated with changes at the genetic level that in turn is reflected by the altered expression of proteins related to cell cycle, proliferation, and apoptosis. Expression of p53 tumor suppressor gene is one of the common findings in human cancers including the oral cancer. Therefore, the early detection of potentially malignant OSMF has been crucial in the inhibition of oral cancer. To determine the main pathological logical factors and expression of aberrant p53 in OSMF, oral squamous cell carcinomas (OSCC) and in normal patients, to study correlation between p53 expression with clinical staging and histological grading of OSMF. An immunohistochemical (IHC) study was performed for p53 expression on 35 cases of OSMF, 10 cases of OSCC with history of habits and 10 normal patients without any habits. The expression of p53 showed a significant difference between normal oral mucosa, OSMF and OSCC samples. The study demonstrated a high incidence of p53 over expression in OSMF and OSCC. The results indicate that p53 over expression may play a role in pathogenesis of OSMF and in the development of Oral squamous cell carcinoma. With early detection of the high-risk patients with OSMF, we can expect to develop more intensive treatment modalities, leading to the reduction in cancer transformation rate from OSMF.

Tralucent and Pellucid-Clear Cell Adenocarcinoma Uterine Cervix

Clear cell adenocarcinoma of uterine cervix is predominantly comprised of clear cells or hobnail cells articulating distinct architectural patterns as solid, tubulocystic or papillary. Tumour cell cytoplasm is clear, eosinophilic with intracytoplasmic hyaline globules and enhanced nuclear grade. A historic association with intrauterine diethylstilbestrol (DES) exposure is enunciated. Sporadic overexpression of p53 tumour suppressor gene may be observed. Neoplasm manifests with vaginal bleeding, postcoital bleeding or abnormal vaginal discharge. Cytological smears exhibit sheets, clusters or papillae of tumour cells permeated with delicate, vacuolated, glycogen rich or finely granular cytoplasm, enlarged, pale, spherical nuclei with prominent nucleoli or naked nuclei with tigroid background composed of granular, reticulated substance. Clear cell adenocarcinoma appears immune reactive to pan-cytokeratin as AE1 / AE3, CAM5.2, CK7, CK8, CK18, CK19, HNF1β, Napsin A, Ki67 or epithelial membrane antigen (EMA). Tumefaction requires segregation from neoplasms such as microglandular hyperplasia, Arias-Stella reaction, primary alveolar soft part sarcoma, mesonephric adenocarcinoma, metastatic clear cell renal cell carcinoma, endometrioid carcinoma, serous carcinoma, squamous cell carcinoma, urothelial carcinoma, adenosis, endometrioid adenocarcinoma with clear cell or secretory change, gastric subtype of endocervical adenocarcinoma or yolk sac tumours of uterine cervix. Neoplasm may be preliminarily subjected to radical hysterectomy with pelvic lymphadenectomy or fertility sparing radical trachelectomy.

PPARα activator irbesartan suppresses the proliferation of endometrial carcinoma cells via SREBP1 and ARID1A.

Endometrial carcinoma (EMC) is associated with obesity; however, the underlying mechanisms have not yet been elucidated. Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that is involved in lipid, glucose, and energy metabolism. PPARα reportedly functions as a tumor suppressor through its effects on lipid metabolism; however, the involvement of PPARα in the development of EMC remains unclear. The present study demonstrated that the immunohistochemical expression of nuclear PPARα was lower in EMC than in normal endometrial tissues, suggesting the tumor suppressive nature of PPARα. A treatment with the PPARα activator, irbesartan, inhibited the EMC cell lines, Ishikawa and HEC1A, by down-regulating sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FAS) and up-regulating the tumor suppressor genes p21 and p27, antioxidant enzymes, and AT-rich interaction domain 1A (ARID1A). These results indicate the potential of the activation of PPARα as a novel therapeutic approach against EMC.

Radiation-Induced Chromosome Instability in WTK1 and TK6 Human Lymphoblastoid Cells

The effects of ionizing radiation on single nucleotide polymorphism (SNP) copy number variations between TK6 and WTK1 cell lines are described herein. Specifically, the integrity of the chromosomes for two WIL2-derived lymphoblastoid cell lines (TK6 and WTK1) was analyzed in the presence and absence of ionizing radiation. WTK1 cells contain a p53 mutation, whereas the TK6 cell line has the native p53 tumor-suppressor gene. Each cell line was isolated post-irradiation for SNP analysis, which showed significant, genome-wide impacts on both cell lines; for the mutant WTK1 sample, there were a total of 48 gene deletions and no gene amplifications, whereas for the wild-type TK6 sample, there were 217 gene deletions and 9 gene amplifications. It appears that both cell lines are affected in the areas of cell-cycle control, but that other affected areas differ significantly between the two.

Genetic mutations in the molecular pathogenesis of gastrointestinal stromal tumor

Gastrointestinal stromal tumors are mesenchymal tumors which predominantly originate from the interstitial cells of Cajal in the intestinal lining. Around ~85% of malignant GISTs possess activating mutations in the tyrosine kinase receptors KIT or PDGFRA. The driver mutations in genes other than KIT or PDGFRA account for around 15% GISTs and belong to highly heterogeneous groups called wild-type GISTs. Around 20–40% of WT-GISTS are deficient for the succinate dehydrogenase complex (SDHA, SDHB, SDHC, SDHD). Mutations in SDH cause the accumulation of oncometabolite succinate that increases the level of HIF1α which enhances the transcription of several genes including IGF1, IGF2, and VEGF inducing the proliferation of the cancer cells. The remaining WT-GISTS are associated with mutations in BRAF, loss-of-function of NF1, hyperactivation FGFR, inactivation of tumor suppressor genes (p53 and dystrophin), and mutations in DNA damage response genes such as RAD51 and BRCA2 which results in the activation of the PI3K/mTOR or RAS/RAF/MAPK signaling cascade. Therefore, understanding the mutational status and molecular characterization of GIST plays a very crucial role in the overall management of GIST.

Syntaxin-6, a Reliable Biomarker for Predicting the Prognosis of Patients with Cancer and the Effectiveness of Immunotherapy

Syntaxin-6 (STX6), a vesicular transport protein, is a direct target of the tumor suppressor gene P53, supporting cancer growth dependent on P53. However, STX6's function in the tumor microenvironment has yet to be reported. In this research, we comprehensively explored the role of the oncogene STX6 in pan-cancer by combining data from several databases, including the Cancer Genome Atlas, CPTAC, cBioPortal, and TIMER. Then, we verified the carcinogenic effect of STX6 in hepatocellular carcinoma (HCC) and colorectal cancer (CRC) through a series of experiments in vitro and in vivo. Bioinformatics analysis demonstrated that STX6 is an oncogene for several cancers and is mainly involved in the cell cycle, epithelial-mesenchymal transition, oxidative phosphorylation, and tumor immune modulation, especially for tumor-associated fibroblasts (CAFs) and NKT cells. Additionally, a high level of STX6 could indicate patients' resistance to immunotherapy. Our own data indicated that the STX6 level was upregulated in HCC and CRC. Knockdown of the STX6 levels could arrest the cell cycle and restrain cell proliferation, migration, and invasion. RNA-seq indicated that STX6 was significantly involved in pathways for cancer, such as the MAPK signal pathway. In a mouse model, knockdown of STX6 inhibited tumor growth and potentiated anti-PD-1 efficacy. In light of the essential roles STX6 plays in carcinogenesis and cancer immunology, it has the potential to be a predictive biomarker and a target for cancer immunotherapy.