Therapeutic targeting of Syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers.

The therapeutic benefit of recently developed mutant KRAS (mKRAS) inhibitors has been limited by the rapid onset of resistance. Here, we aimed to delineate the mechanisms underlying acquired resistance to mKRAS inhibition and identify actionable targets for overcoming this clinical challenge. Previously, we identified Syndecan-1 (SDC1) as a key effector for pancreatic cancer progression whose surface expression is driven by mKRAS. By leveraging both pancreatic and colorectal cancer models, we found that surface SDC1 expression was initially diminished upon mKRAS inhibition, but recovered in tumor cells that bypass mKRAS dependency. Functional studies showed that these tumors depended on SDC1 for survival, further establishing SDC1 as a driver for the acquired resistance to mKRAS inhibition. Mechanistically, we revealed that the YAP1-SDC1 axis was the major driving force for bypassing mKRAS dependency to sustain nutrient salvage machinery and tumor maintenance. Specifically, YAP1 activation mediated the recovery of SDC1 localization on cell surface that sustained macropinocytosis and enhanced the activation of multiple RTKs, promoting resistance to KRAS-targeted therapy. Overall, our study has provided the rationale for targeting the YAP-SDC1 axis to overcome resistance to mKRAS inhibition, thereby revealing new therapeutic opportunities for improving the clinical outcome of patients with KRAS-mutated cancers.

Recent advances of m6A methylation in skeletal system disease.

Skeletal system disease (SSD) is defined as a class of chronic disorders of skeletal system with poor prognosis and causes heavy economic burden. m6A, methylation at the N6 position of adenosine in RNA, is a reversible and dynamic modification in posttranscriptional mRNA. Evidences suggest that m6A modifications play a crucial role in regulating biological processes of all kinds of diseases, such as malignancy. Recently studies have revealed that as the most abundant epigentic modification, m6A is involved in the progression of SSD. However, the function of m6A modification in SSD is not fully illustrated. Therefore, make clear the relationship between m6A modification and SSD pathogenesis might provide novel sights for prevention and targeted treatment of SSD. This article will summarize the recent advances of m6A regulation in the biological processes of SSD, including osteoporosis, osteosarcoma, rheumatoid arthritis and osteoarthritis, and discuss the potential clinical value, research challenge and future prospect of m6A modification in SSD.

KRAS inhibition activates an actionable CD24 'don't eat me' signal in pancreas cancer.

KRAS G12C inhibitor (G12Ci) has produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment is therefore crucial. To better understand the tumor biology of the KRAS G12C allele and possible bypass mechanisms, we developed a novel autochthonous KRAS G12C -driven PDAC model. Compared to the classical KRAS G12D PDAC model, the G12C model exhibit slower tumor growth, yet similar histopathological and molecular features. Aligned with clinical experience, G12Ci treatment of KRAS G12C tumors produced modest impact despite stimulating a 'hot' tumor immune microenvironment. Immunoprofiling revealed that CD24, a 'do-not-eat-me' signal, is significantly upregulated on cancer cells upon G12Ci treatment. Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment. Similar findings were observed in KRAS G12D -driven PDAC. Our study reveals common and distinct oncogenic KRAS allele-specific biology and identifies a clinically actionable adaptive mechanism that may improve the efficacy of oncogenic KRAS inhibitor therapy in PDAC. Significance: Lack of faithful preclinical models limits the exploration of resistance mechanisms to KRAS G12C inhibitor in PDAC. We generated an autochthonous KRAS G12C -driven PDAC model, which revealed allele-specific biology of the KRAS G12C during PDAC development. We identified CD24 as an actionable adaptive mechanisms in cancer cells induced upon KRAS G12C inhibition and blocking CD24 sensitizes PDAC to KRAS inhibitors in preclinical models.

[Clinical and radiologic comparison between oblique lateral interbody fusion and minimally invasive transforaminal lumbar interbody fusion for degenerative lumbar spondylolisthesis].

OBJECTIVE: To compare the short-term clinical efficacy and radiologic differences between oblique lateral interbody fusion(OLIF) and minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) for degenerative lumbar spondylolisthesis. METHODS: A retrospective analysis was performed on 58 patients with lumbar spondylolisthesis treated with OLIF or MIS-TLIF from April 2019 to October 2020. Among them, 28 patients were treated with OLIF (OLIF group), including 15 males and 13 females aged 47 to 84 years old with an average age of (63.00±9.38) years. The other 30 patients were treated with MIS-TLIF(MIS-TLIF group), including 17 males and 13 females aged 43 to 78 years old with an average age of (61.13±11.10) years. General conditions, including operation time, intraoperative blood loss, postoperative drainage, complications, lying in bed, and hospitalization time were recorded in both groups. Radiological characteristics, including intervertebral disc height (DH), intervertebral foramen height (FH), and lumbar lordosis angle (LLA), were compared between two groups. The visual analogue scale (VAS) and Oswestry disability index (ODI) were used to evaluate the clinical effect. RESULTS: The operation time, intraoperative blood loss, postoperative drainage, lying in bed, and hospitalization time in OLIF group were significantly less than those in the MIS-TLIF group (P<0.05). The intervertebral disc height and intervertebral foramen height were significantly improved in both groups after the operation (P<0.05). The lumbar lordosis angle in OLIF group was significantly improved compared to before the operation(P<0.05), but there was no significant difference in the MIS-TLIF group before and after operation(P>0.05). Postoperative intervertebral disc height, intervertebral foramen height, and lumbar lordosis were better in the OLIF group than in the MIS-TLIF group (P<0.05). The VAS and ODI of the OLIF group were lower than those of the MIS-TLIF group within 1 week and 1 month after the operation (P<0.05), and there were no significant differences in VAS and ODI at 3 and 6 months after the operation between the two groups(P>0.05). In the OLIF group, 1 case had paresthesia of the left lower extremity with flexion-hip weakness and 1 case had a collapse of the endplate after the operation;in the MIS-TLIF group, 2 cases had radiation pain of lower extremities after decompression. CONCLUSION: Compared with MIS-TLIF, OLIF results in less operative trauma, faster recovery, and better imaging performance after lumbar spine surgery.

Efficacy and safety of subanesthetic doses of esketamine combined with propofol in painless gastrointestinal endoscopy: a prospective, double-blind, randomized controlled trial.

BACKGROUND: Painless gastrointestinal endoscopy is widely used for the diagnosis and treatment of digestive diseases. At present, propofol is commonly used to perform painless gastrointestinal endoscopy, but the high dose of propofol often leads to a higher incidence of cardiovascular and respiratory complications. Studies have shown that the application of propofol combined with ketamine in painless gastrointestinal endoscopy is beneficial to reduce the dosage of propofol and the incidence of related complications. Esketamine is dextrorotatory structure of ketamine with a twice as great anesthetic effect as normal ketamine but fewer side effects. We hypothesized that esketamine may reduce the consumption of propofol and to investigate the safety of coadministration during gastrointestinal endoscopy. METHODS: A total of 260 patients undergoing painless gastrointestinal endoscopy (gastroscope and colonoscopy) were randomly divided into P group (propofol + saline), PK1 group (propofol + esketamine 0.05 mg/kg), PK2 group (propofol + esketamine 0.1 mg/kg), and PK3 group (propofol + esketamine 0.2 mg/kg). Anesthesia was achieved by 1.5 mg/kg propofol with different doses of esketamine. Propofol consumption per minute was recorded. Hemodynamic index, pulse oxygen saturation, operative time, induction time, awakening status, orientation recovery time, adverse events, and Mini-Mental State Examination (MMSE) were also recorded during gastrointestinal endoscopy. RESULTS: Propofol consumption per minute was 11.78, 10.56, 10.14, and 9.57 (mg/min) in groups P, PK1, PK2, and PK3, respectively; compared with group P, groups PK2 and PK3 showed a decrease of 13.92% (P = 0.021) and 18.76% (P = 0.000), respectively. In all four groups, systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), but not pulse oxygen saturation (SpO2) significantly decreased (P = 0.000) immediately after administration of induction, but there were no significant differences between the groups. The induction time of groups P, PK1, PK2, and PK3 was 68.52 ± 18.394, 64.83 ± 13.543, 62.23 ± 15.197, and 61.35 ± 14.470 s, respectively (P = 0.041). Adverse events and psychotomimetic effects were observed but without significant differences between the groups. CONCLUSIONS: The combination of 0.2 mg/kg esketamine and propofol was effective and safe in painless gastrointestinal endoscopy as evidenced by less propofol consumption per minute, shorter induction time, and lower incidence of cough and body movement relative to propofol alone. The lack of significant differences in hemodynamic results, anesthesia-related indices, adverse events, and MMSE results showed the safety to apply this combination for painless gastrointestinal endoscopy. Trial registration This study was registered with China Clinical Trial Registration on 07/11/2020 (registration website: chictr.org.cn; registration numbers: ChiCTR https://clinicaltrials.gov/ct2/show/2000039750 ).

Targeting syndecan-1: new opportunities in cancer therapy.

Syndecan-1 (SDC1, CD138) is one of the heparan sulfate proteoglycans and is essential for maintaining normal cell morphology, interacting with the extracellular and intracellular protein repertoire, as well as mediating signaling transduction upon environmental stimuli. The critical role of SDC1 in promoting tumorigenesis and metastasis has been increasingly recognized in various cancer types, implying a promising potential of utilizing SDC1 as a novel target for cancer therapy. This review summarizes the current knowledge on SDC1 structure and functions, including its role in tumor biology. We also discuss the highlights and limitations of current SDC1-targeted therapies as well as the obstacles in developing new therapeutic methods, offering our perspective on the future directions to target SDC1 for cancer treatment.

Esketamine alleviates postoperative depression-like behavior through anti-inflammatory actions in mouse prefrontal cortex.

The rising incidence of postoperative depression (POD) in recent years has placed a heavy burden on patients' physical and mental health. At this point in time, however, POD pathogenesis remains poorly understood and novel therapeutic strategies are being sought. The present study aimed to clarify esketamine's protective effects and possible mechanisms of action in POD. To this avail, we used an animal model of postoperative depression to analyze behavioral, parameters, plus the inflammatory response in serum and in the medial prefrontal cortex (mPFC). Using immunofluorescence staining, we detected the number of microglia and parvalbumin (PV) in mPFC, and determined changes in neuronal dendritic spine density via Golgi staining. Expression of Iba1, PSD95 and NF-κB was examined by Western blot analysis. Our results show that esketamine can significantly improve depression-like symptoms caused by anesthesia and surgery. In addition, esketamine administration reversed the decrease in the density of PV neurons and restored synaptogenesis in mPFC which had been perturbed by inflammation. The evidence obtained suggests esketamine's anti-inflammatory effects may be mediated by the BDNF/TrkB signaling pathway and possibly by attenuation of the nuclear factor κB (NF-κB) pathway. These data warrant further investigations into the interplay of esketamine, and microglia in the modulation of POD symptomatology.

Chemokines in colon cancer progression.

Colon cancer is a major human cancer accounting for about a tenth of all cancer cases thus making it among the top three cancers in terms of incidence as well as mortality. Metastasis to distant organs, particularly to liver, is the primary reason for associated mortality. Chemokines, the chemo-attractants for various immune cells, have increasingly been reported to be involved in cancer initiation and progression, including in colon cancer. Here we discuss the available knowledge on the role of several chemokines, such as, CCL2, CCL3, CCL5, CXCL1, CXCL2, CXCL8 in colon cancer progression. CCL20 is one chemokine with emerging evidence for its role in influencing colon cancer tumor microenvironment through the documents effects on fibroblasts, macrophages and immune cells. We focus on CCL20 and its receptor CCR6 as promising factors that affect multiple levels of colon cancer progression. They interact with several cytokines and TLR receptors leading to increased aggressiveness, as supported by multitude of evidence from in vitro, in vivo studies as well as human patient samples. CCL20-CCR6 bring about their biological effects through regulation of several signaling pathways, including, ERK and NF-κB pathways, in addition to the epithelial-mesenchymal transition. Signaling involving CCL20-CCR6 has profound effect on colon cancer hepatic metastasis. Combined with elevated CCL20 levels in colon tumors and metastatic patients, the above information points to a need for further evaluation of chemokines as diagnostic and/or prognostic biomarkers.

Regulatory effects of lncRNAs and miRNAs on the crosstalk between autophagy and EMT in cancer: a new era for cancer treatment.

PURPOSE: Autophagy and EMT (epithelial-mesenchymal transition) are the two principal biological processes and ideal therapeutic targets during cancer development. Autophagy, a highly conserved process for degrading dysfunctional cellular components, plays a dual role in tumors depending on the tumor stage and tissue types. The EMT process is the transition differentiation from an epithelial cell to a mesenchymal-like cell and acquiring metastatic potential. There is evidence that the crosstalk between autophagy and EMT is complex in cancer. In recent years, more studies have shown that long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are involved in autophagy, EMT, and their crosstalk. Therefore, accurate understanding of the regulatory mechanisms of lncRNAs and miRNAs in autophagy, EMT and their interactions is crucial for the clinical management of cancers. METHODS: An extensive literature search was conducted on the Google Scholar and PubMed databases. The keywords used for the search included: autophagy, EMT, crosstalk, lncRNAs, miRNAs, cancers, diagnostic biomarkers, and therapeutic targets. This search provided relevant articles published in peer-reviewed journals until 2021. Data from these various studies were extracted and used in this review. RESULTS: The results showed that lncRNAs/miRNAs as tumor inhibitors or tumor inducers could regulate autophagy, EMT, and their interaction by regulating several molecular signaling pathways. The lncRNAs/miRNAs involved in autophagy and EMT processes could have potential uses in cancer diagnosis, prognosis, and therapy. CONCLUSION: Such information could help find and develop lncRNAs/miRNAs based new tools for diagnosing, prognosis, and creating anti-cancer therapies.

USP21 deubiquitinase elevates macropinocytosis to enable oncogenic KRAS bypass in pancreatic cancer.

Activating mutations in KRAS (KRAS*) are present in nearly all pancreatic ductal adenocarcinoma (PDAC) cases and critical for tumor maintenance. By using an inducible KRAS* PDAC mouse model, we identified a deubiquitinase USP21-driven resistance mechanism to anti-KRAS* therapy. USP21 promotes KRAS*-independent tumor growth via its regulation of MARK3-induced macropinocytosis, which serves to maintain intracellular amino acid levels for anabolic growth. The USP21-mediated KRAS* bypass, coupled with the frequent amplification of USP21 in human PDAC tumors, encourages the assessment of USP21 as a novel drug target as well as a potential parameter that may affect responsiveness to emergent anti-KRAS* therapy.

Interaction of microRNAs with sphingosine kinases, sphingosine-1 phosphate, and sphingosine-1 phosphate receptors in cancer.

Sphingosine-1-phosphate (S1P), a pleiotropic lipid mediator, participates in various cellular processes during tumorigenesis, including cell proliferation, survival, drug resistance, metastasis, and angiogenesis. S1P is formed by two sphingosine kinases (SphKs), SphK1 and SphK2. The intracellularly produced S1P is delivered to the extracellular space by ATP-binding cassette (ABC) transporters and spinster homolog 2 (SPNS2), where it binds to five transmembrane G protein-coupled receptors to mediate its oncogenic functions (S1PR1-S1PR5). MicroRNAs (miRNAs) are small non-coding RNAs, 21-25 nucleotides in length, that play numerous crucial roles in cancer, such as tumor initiation, progression, apoptosis, metastasis, and angiogenesis via binding to the 3'-untranslated region (3'-UTR) of the target mRNA. There is growing evidence that various miRNAs modulate tumorigenesis by regulating the expression of SphKs, and S1P receptors. We have reviewed various roles of miRNAs, SphKs, S1P, and S1P receptors (S1PRs) in malignancies and how notable miRNAs like miR-101, miR-125b, miR-128, and miR-506, miR-1246, miR-21, miR-126, miR499a, miR20a-5p, miR-140-5p, miR-224, miR-137, miR-183-5p, miR-194, miR181b, miR136, and miR-675-3p, modulate S1P signaling. These tumorigenesis modulating miRNAs are involved in different cancers including breast, gastric, hepatocellular carcinoma, prostate, colorectal, cervical, ovarian, and lung cancer via cell proliferation, invasion, angiogenesis, apoptosis, metastasis, immune evasion, chemoresistance, and chemosensitivity. Therefore, understanding the interaction of SphKs, S1P, and S1P receptors with miRNAs in human malignancies will lead to better insights for miRNA-based cancer therapy.

Exosomal miR-21 promotes proliferation, invasion and therapy resistance of colon adenocarcinoma cells through its target PDCD4.

Exosomes contain cell-specific collections of bioactive materials including proteins, lipids, and RNAs that are transported to recipient cells to exert their impacts. MicroRNAs (miRNAs) can function as tumor suppressor or oncogenic genes and miR-21 is one of the most frequently up-regulated miRNAs in solid tumors including colon cancer. The aim of this study was to investigate the role of miR-21, secreted from exosomes, in proliferation and invasion of colon cancer, along with the mechanistic details. We used a variety of biochemical techniques including ultracentrifugation-based exosome purification, electron transmission microscopy, western blot and RT-qPCR to detect the expression levels of miR-21 in exosomes purified from culture media of human colonic adenocarcinoma cell lines. We then performed functional and mechanistic studies using three colon cancer cell lines HT29, T84 and LS174 as well as the normal colon epithelial cells CRL1831. miR-21 target PDCD4 was investigated for its role in mediating miR-21 effects. Expression of miR-21 was significantly up-regulated in exosomes of colon cancer cells, compared to the normal human colon epithelial cells. Treatment of colon cancer cells with isolated exosomes or miR-21 led to an increased expression of genes involved in cell proliferation, invasion and extracellular matrix formation. miR-21 targets PDCD4, TPM1 and PTEN were down-regulated by exosomes and silencing of PDCD4 mimicked miR-21 functional effects, even the induced resistance against 5-FU. Our study suggests that targeted inhibition of exosomes, particularly those carrying miR-21, may represent a novel approach for treatment of colorectal cancer.

A review on the efficacy and safety of iodine-125 seed implantation in unresectable pancreatic cancers.

Background: Pancreatic cancers are the common digestive system tumors with poor prognosis and due to its late diagnosis, surgical resection does not remain a viable treatment option in about 80% of patients. Amongst different treatment options, radioactive 125I seed implantation therapy has also emerged as a good alternative in non-resectable pancreatic cancer patients.Purpose: The present review describes the efficacy and safety of iodine-125 seed implantation in unresectable pancreatic cancers in preclinical and clinical studies.Results: In this technique, small radioactive particles are implanted inside the tumor cells to produce the sustain effects. Due to the short radial distance of these radiations, there is a selective and efficient killing of cancer cells without any significant injury to the neighboring cells. Amongst the different methods for implanting 125I seeds in the pancreatic tissues, CT scan or ultrasound-guided percutaneous seed implantation is preferred as it offers shorter operative time, lesser bleeding, early recovery, lesser complications, and low medical costs. The clinical studies have shown that radioactive 125I seed implantation is a good option for the management of local tumor growth, pain palliation, and improvement in the life span of patients suffering from unresectable pancreatic cancer.Conclusion: It may be employed either alone or in combination with cryotherapy, existing chemotherapy, bypass surgery or radiations to achieve the optimal results in these patients. Nevertheless, there is a need to formulate a uniform dose and procedure to achieve homogeneity and develop references for clinical practices.

The roles of PD-1/PD-L1 and its signalling pathway in gastrointestinal tract cancers.

Cancer immunotherapy has been increasingly applied in the treatment of advanced malignancies. Consequently, immune checkpoints have become a major concern. As PD-1 is an important immunomodulatory protein, the blockade of PD-1 and its ligand PD-L1 is a promising tumour immunotherapy for human carcinoma. In this review, we first discuss the role of the PD-1/PD-L1 interaction in gastrointestinal tract cancers. Targeting PD-1 and PD-L1 in immune cells and tumour cells may show remarkable efficiency in gastrointestinal tract cancers. Second, the PD-1/PD-L1-associated signalling pathway involved in cancer immunotherapy in gastrointestinal tract cancers is discussed. Most importantly, this review summarizes the PD-1/PD-L1-targeted immunotherapy combinations with relevant signalling pathways, which may result in a breakthrough for the treatment of gastrointestinal tract cancers, such as gastric cancer, colorectal cancer and liver cancer. Meanwhile, the review provides a deeper insight into the mechanism of checkpoint blockade immunotherapies.

Targeting IFNα to tumor by anti-PD-L1 creates feedforward antitumor responses to overcome checkpoint blockade resistance.

Many patients remain unresponsive to intensive PD-1/PD-L1 blockade therapy despite the presence of tumor-infiltrating lymphocytes. We propose that impaired innate sensing might limit the complete activation of tumor-specific T cells after PD-1/PD-L1 blockade. Local delivery of type I interferons (IFNs) restores antigen presentation, but upregulates PD-L1, dampening subsequent T-cell activation. Therefore, we armed anti-PD-L1 antibody with IFNα (IFNα-anti-PD-L1) to create feedforward responses. Here, we find that a synergistic effect is achieved to overcome both type I IFN and checkpoint blockade therapy resistance with the least side effects in advanced tumors. Intriguingly, PD-L1 expressed in either tumor cells or tumor-associated host cells is sufficient for fusion protein targeting. IFNα-anti-PD-L1 activates IFNAR signaling in host cells, but not in tumor cells to initiate T-cell reactivation. Our data suggest that a next-generation PD-L1 antibody armed with IFNα improves tumor targeting and antigen presentation, while countering innate or T-cell-driven PD-L1 upregulation within tumor.

Eukaryotic translation initiation factor EIF3H potentiates gastric carcinoma cell proliferation.

Eukaryotic translation initiation factor 3 subunit H (EIF3H) is required for the progression of several types of cancer. However, little is known about the function of EIF3H in gastric carcinoma. To address this issue, in the present study, we investigated EIF3H genetic alterations in and expression of EIF3H in gastric cancer tissue samples using cBioPortal and Oncomine databases. Endogenous EIF3H expression was knocked down in MGC80-3 and AGS gastric cancer cell lines by lentivirus-mediated RNA interference. We confirmed the knockdown efficiency by quantitative real-time PCR and western blotting and evaluated the effects of EIF3H silencing on cell proliferation of gastric cancer with the cell viability and colony formation assays and by flow cytometry. The OncoPrint of EIF3H generated using cBioPortal indicated that EIF3H genetic alterations (mutation, deletion and amplification) were present in two gastric cancer sample sets. The Oncomine analysis revealed that EIF3H mRNA level was upregulated in gastric cancer tissues. EIF3H knockdown inhibited cell proliferation and colony formation in gastric cancer lines and led to cell cycle arrest at the G0/G1 phase, while inducing apoptosis via up- and downregulation of pro- and anti-apoptotic factors, respectively. These results indicate that EIF3H can serve as a novel therapeutic target for the clinical treatment of gastric cancer.

Primary malignant mesenchymoma of bladder: Case report and review of the literature.

RATIONALE: Malignant mesenchymoma (MM) is defined as a heterogeneous malignant soft tissue tumor that consists of 2 or more distinctly different mesenchymal components in addition to fibrosarcomatous elements. Bladder MM was rarely reported in the literature and there are only 5 cases of primary bladder MM documented in English literature to date. PATIENT CONCERNS: A 58-year-old male complained of difficulty in urination and intermittent gross hematuria for 3 months. Doppler ultrasound scan revealed an avascular and homogeneous hypoechoic mass measured 6.5 × 9 cm in the bladder. Computed tomography showed a homogeneous solid mass in the bladder. DIAGNOSES: Pathology revealed spindle-shaped tumor and proliferation of poorly differentiated immature mesenchymal cells rich in eosinophilic cytoplasm with hyperchromatic sticklike nuclei. Immunohistochemical examinations were positive for CD117. INTERVENTIONS: The patient was diagnosed with presence of bladder tumor and underwent radical cystectomy; the optimal treatment strategy was reviewed and discussed. OUTCOMES: There was no recurrence or metastasis during a 16-month follow-up. LESSONS: Our case study demonstrated bladder MM with a relatively indolent clinical course. A multidisciplinary approach including surgery, radiotherapy, and chemotherapy may be useful. Radical resection is the most important determinant of clinical outcome. Generally, the clinical outcome and prognosis of mesenchymoma are favorable.

Polymorphisms in the ERCC1 and XPF genes and risk of breast cancer in a Chinese population.

Inherited functional single-nucleotide polymorphisms (SNPs) in DNA repair genes may influence the capability of DNA repair and contribute to the risk of breast cancer. We therefore performed a case-control study to investigate the association of three in excision repair cross-complimentary group 1 (ERCC1) and three in xeroderma pigmentosum complementation group F (XPF) with the risk of breast cancer. Genotyping of ERCC1 (rs2298881, rs3212986, and rs11615) and XPF (rs2276465, rs6498486, and rs2276466) was performed in a 384-well plate format on the MassARRAY(®) platform. Odds ratios and their corresponding 95% confidence intervals were used to assess the effect of each SNP on breast cancer risk. The ERCC1 rs11615 variant A/A genotype was associated with increased breast cancer risk in codominant, dominant, and recessive models, and XPF rs6498486 variant C/C genotype carriers have a significantly increased breast cancer risk in codominant, dominant, and recessive models. Individuals with both the ERCC1 rs11615 A allele and XPF rs6498486 C allele had a heavy increased risk of breast cancer compared to double wild-type homozygotes. The present study shows that the ERCC1 rs11615 and XPF rs6498486 polymorphisms are associated with breast cancer risk in a Chinese population. Further large-scale studies are required to elucidate whether these ERCC1 and XPF SNPs interact with environmental factors in the development of breast cancer.

[ShRNA-mediated silencing of MDM2 inhibits growth of HepG2 hepatocellular carcinoma cells xenografted in nude mice].

OBJECTIVE: To construct a short hairpin (sh)RNA targeting the gene encoding the MDM2 oncoprotein in order to investigate its role in human hepatocellular carcinoma (HCC) and its potential for use as a gene therapy strategy to inhibit HCC growth in vivo. METHODS: Small interfering (si)RNAs were designed targeting the MDM2 gene (siMDM2-1 and siMDM2-2) and unrelated sequences (negative control) and cloned into the expression plasmid pGCSilencer-U6-neo-GFP. A HCC mouse model was established by subcutaneous inoculation of HepG2 cells (2 x 10(6) in 0.2 ml) into 20 nude mice. The inoculated mice were divided into four equal groups for tumor-localized injections of saline, negative control siRNA plasmid, siMDM2-1 plasmid, and siMDM2-2 plasmid. Tumor growth was observed daily (by caliper measurement) for one month, when mice were sacrificed by cervical dislocation. The tumor mass was resected for analysis of tumor inhibition rate (% = [(average tumor weight of control group - average tumor weight of treatment group) / average tumor weight of control group x 100]) and effects on MDM2 and p53 mRNA and protein expression (by reverse transcription- PCR and western blotting, both normalized to beta-actin). Significance of between-group differences was assessed by one-way ANOVA or LSD test; pairwise comparisons were made by the Chi-squared test. RESULTS: siMDM2-1 and siMDM2-2 suppressed the xenografted tumor growth remarkably (60.6% and 54.6% inhibition rates, respectively), significantly reduced the expression ofMDM2 gene (62.8% and 61.6%) and protein (60.7% and 59.5%), and significantly increased p53 gene (47.1% and 45.6%) and protein (45.9% and 44.3%) (all, P < 0.05). CONCLUSION: shRNA-mediated silencing of the MDM2 gene effectively inhibits HCC tumorigenesis of subcutaneously xenografted HepG2 cells in nude mice, and the mechanism may involve p53.

Association between MTHFR Ala222Val (rs1801133) polymorphism and bladder cancer susceptibility: a systematic review and meta-analysis.

Folate metabolism is thought to play an important role in carcinogenesis through its involvement in both DNA methylation and nucleotide synthesis. The association between the MTHFR Ala222Val polymorphism and bladder cancer has been widely reported, however, in general the data from published studies with individually low statistical power were controversial and underpowered. Hence, we performed a meta-analysis to investigate the association between bladder cancer and MTHFR Ala222Val in different inheritance models. Fourteen studies including a total of 3,570 bladder cancer cases and 3,926 controls for MTHFR rs1801133 polymorphism were included in the meta-analysis. Data were extracted from these studies and odds ratios with corresponding 95 % confidence intervals (95 % CI) were computed to estimate the strength of the association. Overall, the MTHFR Ala222Val polymorphism was not associated with the development of bladder cancer in all genetic models (Ala/Ala vs. Val/Val--OR = 0.961, 95 % CI = 0.763-1.209; Ala/Ala vs. Ala/Val--OR = 0.918, 95 % CI = 0.795-1.060--Ala/Val vs. Val/Val--OR = 1.022, 95 % CI = 0.852-1.227; dominant model--OR = 0.998, 95 % CI = 0.869-1.145; recessive model--OR = 0.921, 95 % CI = 0.794-1.069; Ala allele vs. Val allele--OR = 0.957, 95 % CI = 0.857-1.067). In the stratified analyses, no significant associations were found among different descent populations and sources of controls. Our meta-analysis suggests that the MTHFR Ala222Val polymorphism not contributes to the development of bladder cancer.