Emodin induces ferroptosis in colorectal cancer through NCOA4-mediated ferritinophagy and NF-κb pathway inactivation.

Ferroptosis is a new programmed cell death characterized by iron-dependent lipid peroxidation. Targeting ferroptosis is considered a promising strategy for anti-cancer therapy. Recently, natural compound has gained increased attention for their advantage in cancer treatment, and the exploration of natural compounds as ferroptosis inducers offers a hopeful avenue for advancing cancer treatment modalities. Emodin is a natural anthraquinone derivative in many widely used Chinese medicinal herbs. In our previous study, we predicted that the anti-cancer effect of Emodin might related to ferroptosis by using RNA-seq in colorectal cancer (CRC). Thus, in this study, we aim to investigate the molecular mechanism underlying Emodin-mediated ferroptosis in CRC. Cell-based assays including CCK-8, colony formation, EdU, and Annexin V/PI staining were employed to assess Emodin's impact on cell proliferation and apoptosis. Furthermore, various techniques such as FerroOrange staining, C11-BODIPY 581/591 staining, iron, MDA, GSH detection assay and transmission electron microscopy were performed to examine the role of Emodin in ferroptosis. Additionally, specific NCOA4 knockdown cell lines were generated to elucidate the involvement of NCOA4 in Emodin-induced ferroptosis. Moreover, the effects of Emodin on ferroptosis were further confirmed through the application of inhibitors, including Ferrostatin-1, 3-MA, DFO, and PMA. As a results, Emodin inhibited proliferation and induced apoptosis in CRC cells. Emodin could decrease GSH content, xCT and GPX4 expression, meanwhile increasing ROS generation, MDA, and lipid peroxidation, and these effects could reverse by ferroptosis inhibitor, Ferostatin-1, iron chelator DFO, autophagy inhibitor 3-MA and NCOA4 silencing. Moreover, Emodin could inactivate NF-κb pathway, and PMA, an activator of NF-κb pathway could alleviate Emodin-induced ferroptosis in CRC cells. Xenograft mouse model also showed that Emodin suppressed tumor growth and induced ferroptosis in vivo. In conclusion, these results suggested that Emodin induced ferroptosis through NCOA4-mediated ferritinophagy by inactivating NF-κb pathway in CRC cells. These findings not only identified a novel role for Emodin in ferroptosis but also indicated that Emodin may be a valuable candidate for the development of an anti-cancer agent.

ß-Lapachone induces ferroptosis of colorectal cancer cells via NCOA4-mediated ferritinophagy by activating JNK pathway.

ß-Lapachone is a natural product that can promote ROS generation and ultimately triggers tumor cells death by inducing DNA damage. Recent studies have indicated that the targeting of ferroptosis or iron metabolism is a feasible strategy for treating cancer. In this study, bulk RNA-seq analysis suggested that ß-Lapachone might induce ferroptosis in CRC cells. We further tested this hypothesis using a xenograft model of human colorectal cancer as an animal model and in SW620 and DLD-1 of CRC cell lines. Western blot was used to determine the key proteins of ferroptosis (SLC7A11, GPX4), autophagy (LC3B, P62, ATG7), ferritinophagy (NCOA4, FTH1, TFRC), and JNK pathway (p-JNK, JNK, p-c-Jun, c-Jun). The levels of MDA, GSH/GSSG, lipid ROS, and intracellular ferrous iron were determined after ß-Lapachone treatment, and inhibitors of various pathways, including NAC, Ferrostatin-1, DFO, 3-MA, and SP600125 were utilized to explore the molecular mechanism underlying ß-Lapachone-mediated ferroptosis. As the result, we identified that ß-Lapachone inhibited cell proliferation and induced apoptosis, autophagy, and ROS generation. In addition, ß-Lapachone induced ferroptosis as demonstrated by intra-cellular iron overload, increased levels of lipid ROS and MDA. Mechanistically, JNK signaling pathway was involved in ß-Lapachone-induced xCT/GPX4-mediated ferroptosis and NCOA4-mediated ferritinophagy in CRC cells. In vivo experiments in nude mice demonstrated that ß-Lapachone significantly inhibited CRC growth and induced ferroptosis and NCOA4-mediated ferritinophagy. These findings not only identify a novel role for ß-Lapachone in ferroptosis but also indicate that ß-Lapachone may be a valuable candidate for the research and development of anti-cancer therapeutic agents.

NCPAD2 is a favorable predictor of prognostic and immunotherapeutic biomarker for multiple cancer types including lung cancer.

BACKGROUND: Non-SMC condensin I complex subunit D2 (NCAPD2) belongs to the chromosomal structural maintenance family. While the different contribution of NCAPD2 to chromosome in mitosis have been thoroughly investigated, much less is known about the expression of NCAPD2 in pan-cancer. Thus, we used a bioinformatics dataset to conduct a pan-cancer analysis of NCAPD2 to determine its regulatory role in tumors. METHODS: Multiple online databases were analyzed NCAPD2 gene expression, protein level, patient survival and functional enrichment in pan-cancer. Genetic alteration and tumor stemness of NCAPD2 were analyzed using cBioPortal and SangerBox. The GSCA and CellMiner were used to explore the relationship between NCAPD2 and drug sensitivity. The diagnostic value of prognosis was evaluated by ROC curve. Subsequently, the immune infiltration level and immune subtype of NCAPD2 in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) were analyzed using TIMER1 and TISIDB. RESULTS: NCAPD2 gene expression was significantly higher in most cancers and associated with clinical stage and poor prognosis. Genomic heterogeneity of NCAPD2 promoted the occurrence and development of tumors. GO enrichment analysis suggested NCAPD2 might be involved in DNA repair and immune response. NCAPD2 was involved in immune infiltration of LUAD and LUSC. ROC curves showed that NCAPD2 has important prognosis diagnostic value in LUAD and LUSC. Moreover, NCAPD2 was drug sensitive to topotecan, which may be an optimize immunotherapy. CONCLUSIONS: It was found that NCAPD2 was overexpressed in pan-cancers, which was associated with poor outcomes. Importantly, NCAPD2 could be a diagnostic marker and an immune related biomarker for LUAD and LUSC.

miR-590-5p/Tiam1-mediated glucose metabolism promotes malignant evolution of pancreatic cancer by regulating SLC2A3 stability.

BACKGROUND: T lymphoma invasion and metastasis 1 (Tiam1) is a tumor related gene that specifically activates Rho-like GTPases Rac1 and plays a critical role in the progression of various malignancies. Glycolysis plays an important role in cancer progression, it is crucial for supplying energy and producing metabolic end products, which can maintain the survival of tumor cells. As yet, however, the mechanism of Tiam1 in glycolysis reprogramming of pancreatic cancer (PC) remains to be clarified. Here, we investigated the functional role of Tiam1 in PC cell proliferation, metastasis and glycolysis reprogramming. It is expected to provide a new direction for clinical treatment. METHODS: The clinical relevance of Tiam1 was evaluated in 66 patients with PC, the effect of Tiam1 on cell proliferation was detected via 5-Ethynyl-2'-deoxyuridine (EdU) and colony formation. The ability of cell migration was detected by the wound healing and Transwell. Quantitative real time polymerase chain reaction (qRT-PCR) and luciferase reporter gene experiments clarify the regulatory relationship of miR-590-5p inhibiting Tiam1. Detection of the molecular mechanism of Tiam1 regulating glucose metabolism reprogramming in PC by glucose metabolism kit. RNA sequencing and Co-Immunoprecipitation (CoIP) have identified glucose transporter protein 3 (SLC2A3) as a key downstream target gene for miR-590-5p/Tiam1. RESULTS: We found that Tiam1 expression increased in PC tissues and was associated with lymph node metastasis. The silencing or exogenous overexpression of Tiam1 significantly altered the proliferation, invasion, and angiogenesis of PC cells through glucose metabolism pathway. In addition, Tiam1 could interact with the crucial SLC2A3 and promote the evolution of PC in a SLC2A3-dependent manner. Moreover, miR-590-5p was found to exacerbate the PC cell proliferation, migration and invasion by targeting Tiam1. Furthermore, the reversing effects on proliferation, migration and invasion were found in PC cells with miR-590-5p/Tiam1 overexpression after applying glucose metabolism inhibition. CONCLUSIONS: Our findings demonstrate the critical role of Tiam1 in PC development and the miR-590-5p/Tiam1/SLC2A3 signaling pathway may serve as a target for new PC therapeutic strategies.

The CPT1A/Snail axis promotes pancreatic adenocarcinoma progression and metastasis by activating the glycolytic pathway.

Recent studies have demonstrated that CPT1A plays a critical role in tumor metabolism and progression. However, the molecular mechanisms by which CPT1A affects tumorigenicity during PAAD progression remain unclear. In the current research, the bioinformatics analysis and immunohistochemical staining results showed that CPT1A was overexpressed in PAAD tissues and that its overexpression was associated with a shorter survival time in patients with PAAD. Overexpression of CPT1A increased cell proliferation and promoted EMT and glycolytic metabolism in PAAD cells. Mechanistically, CPT1A is able to bind to Snail and facilitate PAAD progression by regulating Snail stability. In summary, our findings revealed Snail-dependent glycolysis as a crucial metabolic pathway by which CPT1A accelerates PAAD progression. Targeting the CPT1A/Snail/glycolysis axis in PAAD to suppress cell proliferation and metastatic dissemination is a new potential treatment strategy to improve the anticancer therapeutic effect and prolong patient survival.

Overexpression of ferritin light chain as a poor prognostic factor for breast cancer.

BACKGROUND: Ferritin light chain (FTL) is involved in tumor progression, but the specific molecular processes by which FTL affects the development of breast cancer (BRCA) have remained unknown. In this research, the clinicopathological significance of FTL overexpression in BRCA was investigated. METHODS: To investigate the role of FTL in BRCA, we utilized multiple online databases to analyse FTL expression levels in BRCA. Next, we reviewed the expression and localization of the FTL protein in BRCA by immunohistochemistry (IHC), Western blot (WB) and immunofluorescence (IF) staining. To assess the impact of FTL on patient prognosis, we conducted Kaplan‒Meier, univariate and multivariate survival analyses. The relationship between FTL and immune infiltration in BRCA was also analysed in the TISCH and SangerBox databases. MTT, malondialdehyde (MDA) and reactive oxygen species (ROS) assays were carried out to investigate the molecular mechanisms of FTL action in BRCA cells. RESULTS: FTL was significantly upregulated in BRCA compared to normal tissues. Its expression significantly linked to histological grade (P = 0.038), PR expression (P = 0.021), Her2 expression (P = 0.012) and Ki-67 expression (P = 0.040) in patients with BRCA. Furthermore, the expression of the FTL protein was higher in the BRCA cell lines than in the normal breast cells and mainly localized in the cytoplasm. Compared to patients with a low level of FTL expression, patients with a high level of FTL expression showed lower overall survival (OS). More convincingly, univariate and multivariate statistical analyses revealed that FTL expression (P = 0.000), ER expression (P = 0.036) and Her2 expression (P = 0.028) were meaningful independent prognostic factors in patients with BRCA. FTL was associated with immune infiltration in BRCA. Functional experiments further revealed that FTL knockdown inhibited the capacity of proliferation and increased the level of oxidative stress in BRCA cells. CONCLUSIONS: Overexpression of FTL was associated with the progression of BRCA. FTL overexpression may become a biomarker for the evaluation of poor prognosis in patients with BRCA.

NQO1 drives glioblastoma cell aggressiveness through EMT induction via the PI3K/Akt/mTOR/Snail pathway.

Glioblastoma multiforme (GBM) is the most frequent and lethal cancer derived from the central nervous system, of which the mesenchymal (MES) subtype seriously influences the survival and prognosis of patients. NAD(P)H: quinone acceptor oxidoreductase 1 (NQO1) serves an important role in the carcinogenesis and progression of various types of cancer; however, the specific mechanism underlying the regulatory effects of NQO1 on GBM is unclear. Thus, the present study aimed to explore the role and mechanism of NQO1 in GBM progression. The results of bioinformatics analysis and immunohistochemistry showed that high expression of NQO1 was significantly related to the MES phenotype of GBM and shorter survival. In addition, MTT, colony formation, immunofluorescence and western blot analyses, and lung metastasis model experiments suggested that silencing NQO1 inhibited the proliferation and metastasis of GBM cells in vitro and in vivo. Furthermore, western blotting showed that the activity of the PI3K/Akt/mTOR signaling pathway was revealed to be inhibited by downregulation of NQO1 expression, whereas it was enhanced by overexpression of NQO1. Notably, co­immunoprecipitation and ubiquitination experiments suggested that Snail was considered an important downstream target of NQO1 in GBM cells. Snail knockdown could eliminate the promoting effect of ectopic NQO1 on the proliferation and invasion of GBM cells, and reduce its effects on the activity of PI3K/Akt/mTOR signaling pathway. These results indicated that NQO1 could promote GBM aggressiveness by activating the PI3K/Akt/mTOR signaling pathway in a Snail­dependent manner, and NQO1 and its relevant pathways may be considered novel targets for GBM therapy.

RSL1D1 knockdown induces ferroptosis and mediates ferrous iron accumulation in senescent cells by inhibiting FTH1 mRNA stability.

Iron metabolism plays an important role in maintaining cellular multiple biological functions. Dysfunction of iron homeostasis-maintaining systems was observed in many diseases, including cancer. Ribosomal L1 domain-containing 1 (RSL1D1) is an RNA-binding protein involved in multiple cellular processes, including cellular senescence, proliferation and apoptosis. However, the regulatory mechanism of RSL1D1 underlying cellular senescence and its biological process in colorectal cancer (CRC) is not clearly understood. Here, we report that RSL1D1 expression is downregulated by ubiquitin-mediated proteolysis in senescence-like CRC cells. RSL1D1, as an anti-senescence factor, is frequently upregulated in CRC, and elevated RSL1D1 prevents CRC cells from senescence-like phenotype, and correlated with poor prognosis of CRC patients. Knockdown of RSL1D1 inhibited cell proliferation, and induced cell cycle arrest and apoptosis. Notably, RSL1D1 plays important roles in regulating iron metabolism of cancer cells. In RSL1D1-knockdown cells, FTH1 expression was significantly decreased, while transferrin receptor 1 expression was increased, leading to intracellular ferrous iron accumulation, which subsequently promoted ferroptosis, indicated by the increased malondialdehyde and decreased GPX4 levels. Mechanically, RSL1D1 directly bounds with 3' untranslated region of FTH1 and subsequently promoted the mRNA stability. Moreover, RSL1D1-mediated downregulation of FTH1 was also observed in H2O2-induced senescence-like cancer cells. Taken together, these findings support RSL1D1 plays an important role in regulating intracellular iron homeostasis in CRC, and suggest that RSL1D1 could be a potential therapeutic target for cancer treatment.

An integrative pan-cancer analysis reveals the carcinogenic effects of NCAPH in human cancer.

BACKGROUND: Non-chromosomal structure maintenance protein condensin complex I subunit H (NCAPH) has been reported to play a regulatory role in a variety of cancers and is associated with tumor poor prognosis. This study aims to explore the potential role of NCAPH with a view to providing insights on pathologic mechanisms. METHODS: The expression of NCAPH in different tumors was explored by The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx). The prognostic value of NCAPH was retrieved through GEPIA and Kaplan-Meier Plotter databases. Tumor Immunity Estimation Resource (TIMER) and Single-Sample Gene Set Enrichment Analysis (GSEA) to search for the association of NCAPH with tumor immune infiltration. The cBioPortal and PhosphoSite Plus databases showed NCAPH phosphorylation status in tumors. Gene set enrichment analysis (GSEA) was performed using bioinformatics. RESULTS: Our findings revealed that NCAPH showed high expression levels in a wide range of tumor types, and was strongly correlated with the prognosis of patients. Moreover, a higher phosphorylation level at S59, S67, S76, S190, S222 and T38 site was discovered in head and neck squamous cell carcinoma (HNSC). NCAPH overexpression was positively correlated with the infiltration level of CD8+T cells and myeloid dendritic infiltration in breast cancer and thymoma. CONCLUSIONS: The up-regulation of NCAPH was significantly correlated with the poor prognosis and immune infiltration in pan-cancer, and NCAPH could be served as a potential immunotherapeutic target for cancers.

The NQO1/p53/SREBP1 axis promotes hepatocellular carcinoma progression and metastasis by regulating Snail stability.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide, and its abnormal metabolism affects the survival and prognosis of patients. Recent studies have found that NAD(P)H quinone oxidoreductase-1 (NQO1) played an important role in tumor metabolism and malignant progression. However, the molecular mechanisms by which NQO1 regulates lipid metabolism during HCC progression remain unclear. In this study, bioinformatics analysis and immunohistochemical results showed that NQO1 was highly expressed in HCC tissues and its high expression was closely related to the poor prognosis of HCC patients. Overexpression of NQO1 promoted the cell proliferation, epithelial-to-mesenchymal transition (EMT) process, and angiogenesis of HCC cells. Luciferase reporter assay further revealed that NQO1/p53 could induce the transcriptional activity of SREBP1, consequently regulating HCC progression through lipid anabolism. In addition, Snail protein was stabilized by NQO1/p53/SREBP1 axis and triggered the EMT process, and participated in the regulatory role of NQO1/p53/SREBP1 axis in HCC. Together, these data indicated that NQO1/SREBP1 axis promoted the progression and metastasis of HCC, and might be a potential therapeutic target for HCC.

miR-21-5p/Tiam1-mediated glycolysis reprogramming drives breast cancer progression via enhancing PFKL stabilization.

T lymphoma invasion and metastasis 1 (Tiam1) as a tumor-associated gene specifically activates Rho-like GTPases Rac1 and implicates in the invasive phenotype of many cancers. Altering the glycolytic pathway is foreseen as a sound approach to trigger cancer regression. However, the mechanism of Tiam1 in breast cancer (BC) glycolysis reprogramming remains to be clarified. Here, we reported the Tiam1 high expression and prognostic significance in BC. In vitro and in vivo experimental assays identified the functional role of Tiam1 in promoting BC cell proliferation, metastasis and glycolysis reprogramming. Mechanistically, we showed for the first time that Tiam1 could interact with the crucial glycolytic enzyme phosphofructokinase, liver type (PFKL) and promote the evolution of BC in a PFKL-dependent manner. Moreover, miR-21-5p was found to exacerbate the BC proliferation and aggression by targeting Tiam1. Altogether, our study highlights the critical role of Tiam1 in BC development and that the miR-21-5p/Tiam1/PFKL signaling pathway may serve as a target for new anti-BC therapeutic strategies.

The molecular mechanism of baicalein repressing progression of gastric cancer mediating miR-7/FAK/AKT signaling pathway.

BACKGROUND: Baicalein (BAI) has a significant anti-cancerous function in the treatment of gastric cancer (GC). Focal adhesion kinase (FAK) is a key regulatory molecule in integrin and growth factor receptor mediated signaling. MicroRNA-7 (miR-7), has been considered as a potential tumor suppressor in a variety of cancers. However, the possible mechanisms by which BAI inhibiting progression of gastric cancer mediating miR-7/FAK/AKT signaling pathway remain unclear. PURPOSE: To investigate the molecular mechanism and effects of BAI inhibiting progression of gastric cancer mediating miR-7/FAK/AKT signaling pathway. METHODS: Gastric cancer cell lines with FAK knockdown and overexpression were constructed by lentivirus transfection. After BAI treatment, the effects of FAK protein on proliferation, metastasis and angiogenesis of gastric cancer cells were detected by MTT, EdU, colony formation, wound healing, transwell and Matrigel tube formation assays. In vivo experiment was performed by xenograft model. Immunofluorescence and western blot assay were used to detect the effects of FAK protein on the expression levels of EMT markers and PI3K/AKT signaling pathway related proteins. qRT-PCR and luciferase reporter assay were used to clarify the targeting relationship between miR-7 and FAK. RESULTS: BAI can regulate FAK to affect proliferation, metastasis and angiogenesis of gastric cancer cells through PI3K/AKT signaling pathway. qRT-PCR showed BAI can upregulated the expression of miR-7 and luciferase reporter assay showed the targeting relationship between miR-7 and FAK. Additionally, miR-7 mediates cell proliferation, metastasis and angiogenesis by directly targeting FAK 3'UTR to inhibit FAK expression. CONCLUSION: BAI repressing progression of gastric cancer mediating miR-7/FAK/AKT signaling pathway.

SPOCK1 promotes metastasis in pancreatic cancer via NF-κB-dependent epithelial-mesenchymal transition by interacting with IκB-α.

BACKGROUND: Sparc/osteonectin, cwcv and kazal-like domain proteoglycan 1 (SPOCK1) has been reported to function as an oncogene in a variety of cancer types. Increasing evidence suggests that SPOCK1 contributes to the metastatic cascade, including invasion, epithelial-mesenchymal transition (EMT) and micro-metastasis formation. As yet, however, the underlying mechanism is not clearly understood. Here, we evaluated the expression and clinicopathological significance of SPOCK1 in primary pancreatic cancer (PC) specimens and explored the mechanisms underlying SPOCK1-mediated PC cell growth and metastasis. METHODS: The clinical relevance of SPOCK1 was evaluated in 81 patients with PC. The effect of SPOCK1 on proliferation, cell cycle progression, EMT and metastasis was examined in vitro and in vivo. The molecular mechanisms involved in SPOCK1-mediated regulation of NF-κB-dependent EMT were assessed in PC cell lines. RESULTS: We found that SPOCK1 expression was increased in PC tissues and was associated with lymph node metastasis. Silencing or exogenous overexpression of SPOCK1 markedly altered the proliferation of PC cells through cell cycle transition. Overexpression of SPOCK1 promoted PC cell migration and invasion by regulating EMT progression. Moreover, we found that SPOCK1 contributes to EMT and metastasis by activating the NF-κB signalling pathway via direct interaction with IκBα. After NF-κB pathway inhibition by BAY11-7082, we found that PC cell motility and EMT induced by SPOCK1 were reversed. CONCLUSION: From our data we conclude that SPOCK1 promotes PC metastasis via NF-κB-dependent EMT by interacting with IκBα. This newly identified mechanism may provide novel clues for the (targeted) treatment of PC patients.

The Significance of SIX1 as a Prognostic Biomarker for Survival Outcome in Various Cancer Patients: A Systematic Review and Meta-Analysis.

Sine Oculis Homeobox Homolog 1 (SIX1) is reported to promote cancer initiation and progression in many preclinical models and is demonstrated in human cancer tissues. However, the correlation between SIX1 and cancer patients' prognosis has not yet been systematically evaluated. Therefore, we performed a systematic review and meta-analysis in various human cancer types and extracted some data from TCGA datasets for further verification and perfection. We constructed 27 studies and estimated the association between SIX1 expression in various cancer patients' overall survival and verified with TCGA datasets. Twenty-seven studies with 4899 patients are include in the analysis of overall, and disease-free survival, most of them were retrospective. The pooled hazard ratios (HRs) for overall and disease-free survival in high SIX1 expression patients were 1.54 (95% CI: 1.32-1.80, P<0.00001) and 1.83 (95% CI: 1.31-2.55, P=0.0004) respectively. On subgroup analysis classified in cancer type, high SIX1 expression was associated with poor overall survival in patients with hepatocellular carcinoma (HR 1.50; 95% CI: 1.17-1.93, P =0.001), breast cancer (HR 1.31; 95% CI: 1.10-1.55, P =0.002) and esophageal squamous cell carcinoma (HR 1.89; 95% CI: 1.42-2.52, P<0.0001). Next, we utilized TCGA online datasets, and the consistent results were verified in various cancer types. SIX1 expression indicated its potential to serve as a cancer biomarker and deliver prognostic information in various cancer patients. More works still need to improve the understandings of SIX1 expression and prognosis in different cancer types.

Prediction of Chemosensitivity in Multiple Primary Cancer Patients Using Machine Learning.

BACKGROUND/AIM: Many cancer patients face multiple primary cancers. It is challenging to find an anticancer therapy that covers both cancer types in such patients. In personalized medicine, drug response is predicted using genomic information, which makes it possible to choose the most effective therapy for these cancer patients. The aim of this study was to identify chemosensitive gene sets and compare the predictive accuracy of response of cancer cell lines to drug treatment, based on both the genomic features of cell lines and cancer types. MATERIALS AND METHODS: In this study, we identified a gene set that is sensitive to a specific therapeutic drug, and compared the performance of several predictive models using the identified genes and cancer types through machine learning (ML). To this end, publicly available gene expression datasets and drug sensitivity datasets of gastric and pancreatic cancers were used. Five ML algorithms, including linear discriminant analysis, classification and regression tree, k-nearest neighbors, support vector machine and random forest, were implemented. RESULTS: The predictive accuracy of the cancer type models were 0.729 to 0.763 on the training dataset and 0.731 to 0.765 on the testing dataset. The predictive accuracy of the genomic prediction models was 0.818 to 1.0 on the training dataset and 0.759 to 0.896 on the testing dataset. CONCLUSION: Performance of the specific gene models was much better than those of the cancer type models using the ML methods. Therofore, the most effective therapeutic drug can be chosen based on the expression of specific genes in patients with multiple primary cancers, regardless of cancer types.

Lipid metabolism regulator human hydroxysteroid dehydrogenase-like 2 (HSDL2) modulates cervical cancer cell proliferation and metastasis.

Human hydroxysteroid dehydrogenase-like 2 (HSDL2) is a potent regulator in cancers and is also involved in lipid metabolism, but the role of HSDL2 in cervical cancer and whether it regulates the progress of cervical cancer through lipid metabolism remains unclear. In this study, we found that the overexpression of HSDL2 was in relation with cervical cancer progression including lymph nodes metastasis and recurrence. HSDL2 could serve as a novel marker of early diagnosis in cervical cancer. HSDL2 also gave impetus to tumorigenesis by initiating and promoting proliferation, invasion and migration of cervical cancer cells (Hela, C33A and SiHa) through EMT. Interestingly, we also searched that HSDL2 participated in oncogenesis by regulating lipid metabolism. In sum, our results gave the novel insight of HSDL2 functions which could be the potential for being the biomarker of prognosis and new target of therapy.

Baicalein Inhibits Gastric Cancer Cell Proliferation and Migration through a FAK Interaction via AKT/mTOR Signaling.

Gastric cancer is a common malignancy worldwide and is associated with high morbidity and mortality rates. However, very little is known about the underlying mechanism in human gastric cancer cells. Baicalein (BAI), a widely used Chinese herbal medicine, has shown anticancer effects on many types of human cancer cell lines. Here, we investigated the molecular mechanisms underlying BAI action on gastric cancer cell proliferation and migration. The results showed that BAI can expressively inhibit cell proliferation, colony-forming ability and migration ability in a dose-dependent manner, while in the meantime inducing cell apoptosis. Additionally, we found that BAI can suppress FAK and the phosphorylation of PI3K, AKT and mTOR in a dose-dependent manner. Furthermore, BAI significantly inhibited tumor growth in a xenograft model. Also, BAI can inhibit the proliferation and migration of gastric cancer cells and the expression of the pathway by downregulating the expression of FAK. In short, we demonstrated that BAI inhibited gastric cancer cell proliferation and migration through FAK interaction via downregulation in AKT/mTOR signaling, which signifies that BAI may be a latent therapeutic factor for the treatment of gastric cancer patients and that FAK might be a hopeful therapy target for the disease.

CD44 enhances adriamycin resistance in chronic myelogenous leukaemia cells K562.

INTRODUCTION: To investigate CD44 effects on the adriamycin-resistant in chronic myelogenous leukaemia cells K562, we explored the role of CD44 in the K562 cells migration and apoptosis. METHODS: GeneChip® screening is used for elucidating various chemoresistance-related gene expression in the adriamycin-resistant leukaemia cells K562/ADR. We constructed K562/CD44 cells by transfection of an EGFP-SV40-CD44 plasmid, and adriamycin-resistant ability was confirmed by detecting migration and apoptosis-related proteins and mRNA expression using Western blotting and Real-time PCR respectively. RESULTS: K562/CD44 cells were generated by the transfection of an EGFP-SV40-CD44 plasmid with high CD44 expression. mRNA expression levels of CD44 and P-glycoprotein (P-gp), along with the proliferation rate, were increased, while the apoptosis rate of K562/CD44 cells was decreased. Migration-associated proteins such as MMP-2 and MMP-9 were upregulated, whereas apoptosis-related protein Bax was downregulated and Bcl-2 protein was not significantly altered in the K562/CD44 cells. CONCLUSIONS: CD44 might be involved in adriamycin resistance via regulation of P-gp, MMP-2, MMP-9, and Bcl-2/Bax.

HSDL2 Acts as a Promoter in Pancreatic Cancer by Regulating Cell Proliferation and Lipid Metabolism.

BACKGROUND: Pancreatic cancer (PC) is a leading cause of cancer mortality worldwide. Hydroxysteroid dehydrogenase like protein 2 (HSDL2) is overexpressed in a variety of malignant tumors and is might be closely related to the development of cancer. It also regulates different metabolism and signaling pathways. PURPOSE: The purpose of this research was to find HSDL2 expression levels and investigate its underlying molecular mechanism in PC. PATIENTS AND METHODS: In the present study, a total of 66 PC samples and 54 normal tissues were used to examine the expression of HSDL2. In order to gain a broader insight into the molecular mechanism of HSDL2 in PC, the HSDL2 siRNA sequences were transfected into PC cell lines (Bxpc-3 and Panc-1), respectively. Cell proliferation was measured by MTT, colony formation assay and EdU assays. Furthermore, the lipid metabolism process was evaluated by triglyceride and phospholipid assay kits, BODIPY 493/503 staining and the expression of several pivotal lipid metabolic enzymes in PC. RESULTS: In this study, HSDL2 was highly expressed in PC and connected with shorter overall survival. When HSDL2 was silenced, the cell proliferation was significantly reduced, and the lipid metabolism was further inhibited. CONCLUSION: High expression of HSDL2 plays an important role in the progression of PC and might be a potential new biomarker of poor prognosis as well as a therapeutic target in the future.