AXL inhibition prevents RPA2/CHK1-mediated homologous recombination to increase PARP inhibitor sensitivity in hepatocellular carcinoma.

Homologous recombination defects (HRD) render cells fail to repair DNA double-strand break (DSB), which causes synthetic lethality in these cells with punch by poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi). Here, we reveal a receptor tyrosine kinase, AXL, whose inhibition leads to HRD in hepatocellular carcinoma (HCC) cells. AXL is upregulated in HCC tumors, which is positively correlated with low survival rates. AXL knockdown or AXL inhibition by bemcentinib reduces HR efficiency in HCC cells, and AXL plays its role in HR repair through its kinase activity. Furthermore, we find that AXL interacts with RPA2, enhancing the recruitment of RPA2 to DNA damage sites. Mechanistically, AXL promotes the tyrosinization of RPA2 at tyrosine 9, promoting the phosphorylation of CHK1, thereby strengthens the HR repair ability in HCC cells to resist DNA damage. In conclusion, our results reveal that AXL is a promising therapeutic biomarker for HCC patients, and present that targeting AXL-RPA2-CHK1 pathway together with PARP inhibitor will be effective therapeutic strategy in HCC.

Evaluating somatosensory evoked potentials in predicting treatment outcomes for thoracolumbar spinal compression fractures using closed reduction and over-extension techniques.

OBJECTIVE: To evaluate the predictive value of somatosensory evoked potentials (SEPs) for the efficacy of closed reduction combined with over-extension reduction technique (PVP) in managing thoracolumbar spinal compression fractures. METHODS: Data were collected from 125 patients who underwent closed reduction with PVP and SEP monitoring from February 2021 to July 2023. We evaluated surgery success rates, incidence of bone cement leakage, and patient recovery outcomes including vertebral anterior height, Oswestry Disability Index (ODI), and Cobb angle restoration. SEP results were analyzed to categorize patients into effective and ineffective treatment groups. Differences in SEP waveforms between these groups were examined, and ROC analysis was used to assess the predictive value of these differences. Multivariate logistic regression was employed to identify risk factors affecting treatment efficacy. RESULTS: Post-treatment assessments showed significant improvements in vertebral anterior height, ODI, and Cobb angle. SEP monitoring correlated well with intraoperative findings and physical examinations. During reduction, changes in SEP latency and amplitude were noted in 37 patients, with 7 patients meeting SEP amplitude alarm criteria, which normalized after adjustments. During PVP, 28 patients exhibited SEP amplitude fluctuations and 5 experienced a 30% reduction in amplitude following initial cement injection, with no significant latency changes. Treatment was deemed effective in 93 patients and ineffective in 32. SEP amplitudes during vertebral compression and PVP were significantly lower in the effective group (P<0.05). The AUC for predicting treatment efficacy was 0.819 and 0.859, respectively. Multivariate analysis revealed low preoperative vertebral compression ratio, number of fractures, and abnormal SEP amplitudes as independent risk factors for treatment outcomes. CONCLUSION: SEP monitoring provides an accurate reflection of spinal cord function during closed reduction with PVP, aiding in predicting treatment safety and efficacy. The use of SEP monitoring is thus recommended for clinical application in this context.

PTOV1-AS1 desensitizes colorectal cancer cells to 5-FU through depressing miR-149-5p to activate the positive feedback loop with Wnt/ß-catenin pathway.

5-Fluorouracil is a commonly used chemotherapy drug for colorectal cancer. Resistance to 5-Fluorouracil remains a challenge. This research aimed to explore the mechanism of 5-Fluorouracil resistance in colorectal cancer. RT-qPCR and Western blot were used to determine the RNA and protein expression in both cells and exosome. Assays in vitro and in vivo were performed to measure the role of miR-149-5p in colorectal cancer cells. RIP, luciferase activity report, and RNA pulldown assay were applied to detect the association of PTOV1-AS1, SUV39H1, miR-149-5p, and FOXM1. MiR-149-5p was down-expressed in 5-Fluorouracil-resistant cells. MiR-149-5p enhanced the effectiveness of 5-Fluorouracil both in vitro and in vivo. Sensitive colorectal cancer cells released exosomal miR-149-5p to sensitize resistant cells to chemotherapy. Mechanistically, miR-149-5p targeted the FOXM1 to inactivate Wnt/ß-catenin pathway, and PTOV1-AS1 recruited SUV39H1 to suppress miR-149-5p transcription, in turn activating Wnt/ß-catenin pathway, and forming a positive feedback loop with FOXM1. PTOV1-AS1 inhibits miR-149-5p by a positive feedback loop with FOXM1-mediated Wnt/ß-catenin pathway, which provides insights into a potential novel target for enhancing the effectiveness of chemotherapy in colorectal cancer patients.

Spermine synthase (SMS) serves as a prognostic biomarker in head and neck squamous cell carcinoma: a bioinformatics analysis.

Background: Head and neck squamous cell carcinoma (HNSC) is an aggressive type of cancer that lacks early detection, and therefore, has a low 5-year survival rate. The spermine synthase (SMS) gene has been shown to be associated with Snyder-Robinson syndrome and poor prognosis of multiple cancers; however, its regulatory role in HNSC has never been investigated. Therefore, we explored the potential predictive value of SMS in HNSC. Methods: We explored the association between SMS expression and clinicopathological parameters of HNSC patients by using data from The Cancer Genome Atlas datasets (TCGA). The prognostic value of SMS was evaluated using the Kaplan-Meier plotter, Gene Expression Profiling Interactive Analysis (GEPIA) 2 and univariate and multivariate Cox regression analyses. We further used gene set enrichment analysis (GESA) to investigate the potential roles of SMS in HNSC prognosis and Tumor Immunity Estimation Resource 2.0 (TIMER2.0) to analyze the correlation between immune cell infiltration and SMS expression. Finally, starBase was used to screen out prognosis-associated non-coding RNA genes to constructed the competing endogenous RNA (ceRNA) network. Co-expression and survival analyses were used to identify the ceRNA network's effect on HNSC prognosis. Results: We found that SMS expression was increased in HNSC compared with normal tissues (P<0.05). In addition, SMS expression was associated with tumor grade (P=0.006), N stage (P=0.001), and prognosis. Survival analysis revealed that high expression of SMS showed worse overall survival (OS) (HR =1.4, P=0.01) and worse disease-free survival (DFS) (HR =1.5, P=0.014). Multivariate Cox analysis further supported the prognostic value of SMS in HNSC (HR =1.006636, P=0.0056). GESA showed that SMS was involved in metabolism- and immune-related pathways. The immune infiltration analyses results showed a decrease in the landscape of immune cell infiltration with high SMS expression and SMS deletion in HNSC. Finally, a ceRNA network (SMS/hsa-miR-23b-3p/KTN1-AS1 and VPS9D1-AS axis) was constructed based on the co-expression and survival analyses in HNSC. Conclusions: Our findings first revealed that SMS functioned as a potential prognostic biomarker and provide insights into the molecular mechanisms of its function in HNSC. The use of SMS may be powerful for determining worse prognosis HNSC patients.

PHF5A promotes colorectal cancerprogression by alternative splicing of TEAD2.

Dysregulated alternative splicing (AS) plays critical roles in driving cancer progression, and the underlying mechanisms remain largely unknown. Here, we demonstrated that PHF5A, a component of U2 small nuclear ribonucleoproteins, was frequently upregulated in colorectal cancer (CRC) samples and associated with poor prognosis. PHF5A promoted proliferation and metastasis of CRC cells in vitro and in vivo. Transcriptomic analysis identified PHF5A-regulated AS targets and pathways. Particularly, PHF5A induced TEAD2 exon 2 inclusion to activate YAP signaling, and interference of TEAD2-L partially reversed the PHF5A-mediated tumor progression. Pharmacological inhibition of PHF5A using pladienolide B had potent antitumor activity. Collectively, these data revealed the oncogenic role of PHF5A in CRC through regulating AS and established PHF5A as potential therapeutic target.

FAP-Targeted Photodynamic Therapy Mediated by Ferritin Nanoparticles Elicits an Immune Response against Cancer Cells and Cancer Associated Fibroblasts.

Cancer-associated fibroblasts (CAFs) are present in many types of tumors and play a pivotal role in tumor progression and immunosuppression. Fibroblast-activation protein (FAP), which is overexpressed on CAFs, has been indicated as a universal tumor target. However, FAP expression is not restricted to tumors, and systemic treatment against FAP often causes severe side effects. To solve this problem, a photodynamic therapy (PDT) approach was developed based on ZnF16Pc (a photosensitizer)-loaded and FAP-specific single chain variable fragment (scFv)-conjugated apoferritin nanoparticles, or αFAP-Z@FRT. αFAP-Z@FRT PDT efficiently eradicates CAFs in tumors without inducing systemic toxicity. When tested in murine 4T1 models, the PDT treatment elicits anti-cancer immunity, causing suppression of both primary and distant tumors, i.e. abscopal effect. Treatment efficacy is enhanced when αFAP-Z@FRT PDT is used in combination with anti-PD1 antibodies. Interestingly, it is found that the PDT treatment not only elicits a cellular immunity against cancer cells, but also stimulates an anti-CAFs immunity. This is supported by an adoptive cell transfer study, where T cells taken from 4T1-tumor-bearing animals treated with αFAP PDT retard the growth of A549 tumors established on nude mice. Overall, our approach is unique for permitting site-specific eradication of CAFs and inducing a broad spectrum anti-cancer immunity.

Plasma Cell Myeloma Type Posttransplant Lymphoproliferative Disorder in an 18-Month-Old Heart Transplant Recipient: Case Report and Review of the Literature.

Plasma cell myeloma type posttransplant lymphoproliferative disorder (PTLD) is a rare subtype of monomorphic B-cell/plasmacytic-type PTLD. Only 10 cases of monomorphic plasmacytic-type PTLD have been previously reported in pediatric transplant recipients (kidney, liver, small bowel-liver, and heart). We present a case of Epstein-Barr virus positive monomorphic plasma cell myeloma type PTLD that developed 10 months after cardiac transplant in an 18-month-old boy. The bone marrow showed replacement by about 20% to 40% lambda-restricted plasmacytoid lymphocytes and plasma cells (by immunohistochemistry and flow cytometry, respectively). His serum free lambda to kappa light chain ratio was >300, comparable to that seen in myeloma in nontransplant patients. The neoplastic cells were Epstein-Barr virus small RNA positive by in situ hybridization. He was treated with rituximab in combination with ganciclovir, intravenous immune globulin, and discontinuation of immunosuppressants. However, he succumbed to septic shock and multiorgan failure 1 month after diagnosis.

Hollow mesoporous carbon nanospheres for imaging-guided light-activated synergistic thermo-chemotherapy.

Carbon-based light-activated materials can absorb optical energy to generate photoacoustic (PA) signals for imaging or transduce optical photons to thermal energy, which holds great promise for biomedical applications. Herein, we synthesize hollow and mesoporous carbon nanospheres (HMCNs) with uniform size on a large scale. The properties of hollow cavity and mesoporous structures make the HMCNs achieve high drug loading (480 mg DOX per g HMCNs). The present intense near infrared (NIR) absorbance achieves excellent photoacoustic imaging ability and photothermal conversion efficacy (32.0%). More interestingly, the encapsulated drugs can have a triggered release under NIR irradiation. The investigations in vitro and in vivo demonstrate that HMCNs have excellent biocompatibility, and accumulate in tumors by the enhanced permeability and retention (EPR) effect. Moreover, under NIR irradiation, in vivo evaluation shows that HMCNs can perform strong PA imaging, and induce great tumor inhibition by the combination of chemotherapy and PTT under the guidance of photoacoustic imaging. The present study provides new insight for design of novel biocompatible light-activated carbons for cancer nanotheranostics.

Clinical characterization and mutation spectrum in patients with familial adenomatous polyposis in China.

BACKGROUND AND AIM: Familial adenomatous polyposis (FAP) is the most common adenomatous polyposis syndrome. Patients with FAP are screened for germline mutations of two genes, APC and MUTYH. However, limited data exist on the clinical characterization and genotypic spectrum of FAP in China. This study was aimed to determine APC and MUTYH mutational status in a small cohort of FAP probands in China and to characterize the genotype-phenotype correlation in mutated patients. METHODS: Mutation screening of 46 unrelated probands was performed using multigene panels by next-generation sequencing. Clinical data of the index were used to assess genotype-phenotype correlations. RESULTS: Overall, 42 out of 46 (91.30%) unrelated probands found mutations, including 35 (76.09%) with APC mutations, 3 (6.52%) with MUTYH mutations, and 4 (8.70%) with both APC and MUTYH mutations. Ten APC genetic alterations variants were novel. The hereditary pattern of the family with both APC and MUTYH mutations was autosomal dominant inheritance. Upper gastrointestinal polyp was the most common extracolonic manifestations. The onset time for patients with both APC and MUTYH mutations was earlier than MUTYH mutation carriers and similar to APC mutation carriers. But the age of carcinogenesis for patients with both APC and MUTYH mutations was later than APC mutation carriers and similar to MUTYH mutation carriers. CONCLUSION: In this study, we show the importance of using multigene panels that allow for a parallel comprehensive screening. We suggest that genetic testing of patients with suspected adenomatous polyposis syndromes should include APC and MUTYH gene mutation analyses simultaneously.

Human Mitotic Centromere-Associated Kinesin Is Targeted by MicroRNA 485-5p/181c and Prognosticates Poor Survivability of Breast Cancer.

PURPOSE: This study aims to evaluate the prognostic value of human Mitotic Centromere-Associated Kinesin (MCAK), a microtubule-dependent molecular motor, in breast cancers. The posttranscriptional regulation of MCAK by microRNAs will also be explored. METHODS: The large-scale gene expression datasets of breast cancer (total n=4,677) were obtained from GEO, NKI, and TCGA database. Kaplan-Meier and Cox analyses were used for survival analysis. MicroRNAs targeting MCAK were predicted by bioinformatic analysis and validated by a dual-luciferase reporter assay. RESULTS: The expression of MCAK was significantly associated with aggressive features of breast cancer, including tumor stage, Elston grade, and molecular subtypes, for global gene expression datasets of breast cancer (p<0.05). Overexpression of MCAK was significantly associated with poor outcome in a dose-dependent manner for either ER-positive or ER-negative breast cancer. Evidence from bioinformatic prediction, coexpression assays, and gene set enrichment analyses suggested that miR-485-5p and miR-181c might target MCAK and suppress its expression. A 3'UTR dual-luciferase target reporter assay demonstrated that miR-485-5p and miR-181c mimics specifically inhibited relative Firefly/Renilla luciferase activity by about 50% in corresponding reporter plasmids. Further survival analysis also revealed that miR-485-5p (HR=0.59, 95% CI 0.37-0.92) and miR-181c (HR=0.54, 95% CI 0.34-0.84) played opposite roles of MCAK (HR=2.80, 95% CI 1.77-4.57) and were significantly associated with better outcome in breast cancers. CONCLUSION: MCAK could serve as a prognostic biomarker for breast cancers. miR-485-5p and miR-181c could specifically target and suppress the MCAK gene expression in breast cancer cells.

Activation of CD3+ T cells by Helicobacter pylori DNA vaccines in potential immunotherapy of gastric carcinoma.

Most of gastric carcinoma (GC) is attributed to infection by Helicobacter pylori (H. pylori) but there is increasing evidence that the positive H. pylori status correlates with better prognosis in GC. The H. pylori-induced cellular immune response may suppress cancer and in this work, recombinant pcDNA3 plasmids encoding various fragments of H. pylori virulence genes of cagA, vacA and babA are constructed and combined into groups to immunize BALB/c mice. The activated splenic CD3+ T cells are purified and the anticancer effects are investigated in vitro and in vivo. The H. pylori DNA vaccines induce a shift in the response from Th1 to Th2 that mimicks the immune status in patients of GC with chronic H. pylori infection. The stimulated CD3+ T cells inhibit the growth of human GC cells in vitro and adoptive transfusions of the CD3+ T cells suppress the growth of GC xenograft in vivo. The effects may be caused by the larger ratios of infiltrated CD8+/CD4+ T cells, reduced infiltration of regulatory FOXP3+ T cells, and enhanced apoptosis induced by upregulation of Caspase-9/Caspase-3 and downregulation of Survivin. Our results reveal the potential immunotherapeutic value of H. pylori vaccine-activated CD3+ T cells in those with advanced GC.

Kaempferol Suppresses Proliferation and Induces Cell Cycle Arrest, Apoptosis, and DNA Damage in Breast Cancer Cells.

Kaempferol is a flavonoid that has been extensively investigated owing to its antitumor effects. Nevertheless, little is known about its underlying mechanisms of action. We aimed to explore the role of kaempferol in breast cancer (BC), and thus we investigated how kaempferol suppresses the growth of BC cells. The cells were treated with kaempferol, and the effects on multiple cancer-associated pathways were evaluated. The MTS assay was used to study the cell growth inhibition induced by kaempferol. The cell cycle was analyzed by flow cytometry. Western blotting was used to analyze cellular apoptosis and DNA damage. We found that the proliferation of the triple-negative BC (TNBC) MDA-MB-231 cells was suppressed effectively by kaempferol. Interestingly, the suppressive effect of kaempferol on cell proliferation was stronger in MDA-MB-231 cells than in the estrogen receptor-positive BT474 cell line. Furthermore, after the treatment with kaempferol for 48 h, the population of cells in the G1 phase was significantly reduced, from 85.48% to 51.35%, and the population of cells in the G2 phase increased markedly from 9.27% to 37.5%, which indicated that kaempferol contributed to the induction of G2/M arrest. Kaempferol also induced apoptosis and DNA damage in MDA-MB-231 cells. Kaempferol increased the expression levels of γH2AX, cleaved caspase 9, cleaved caspase 3, and p-ATM compared to those of the control group. Collectively, these results showed that kaempferol may be a potential drug for the effective treatment of TNBC.

Dysregulation of miR-6868-5p/FOXM1 circuit contributes to colorectal cancer angiogenesis.

BACKGROUND: Transcription factor forkhead box M1 (FOXM1) is a crucial regulator in colorectal cancer (CRC) progression. However, the regulatory mechanisms causing dysregulation of FOXM1 in CRC remain unclear. METHODS: Dual-luciferase reporter assay was conducted to determine FOXM1 as miR-6868-5p target. The function of miR-6868-5p and FOXM1 in CRC angiogenesis was verified in vitro. Intratumoral injection model was constructed to explore the effect of miR-6868-5p on angiogenesis in vivo. Chromatin immunoprecipitation assays were used to assess direct binding of H3K27me3 to the miR-6868 promoter. RESULTS: Through integrated analysis, we identified miR-6868-5p as the potent regulator of FOXM1. Overexpression of miR-6868-5p in CRC cells inhibited the angiogenic properties of co-cultured endothelial cells, whereas silencing of miR-6868-5p had opposite effects. In vivo delivery of miR-6868-5p blocked tumor angiogenesis in nude mice, resulting in tumor growth inhibition. Rescue of FOXM1 reversed the effect of miR-6868-5p on tumor angiogenesis. Further mechanistic study revealed that FOXM1 promoted the production of IL-8, which was responsible for the miR-6868-5p/FOXM1 axis-regulated angiogenesis. Reciprocally, FOXM1 inhibited miR-6868-5p expression through EZH2-mediated H3K27me3 on miR-6868-5p promoter, thus forming a feedback circuit. Clinically, the level of miR-6868-5p was downregulated in CRC tissues and inversely correlated with microvessel density as well as levels of FOXM1 and IL-8 in tumor specimens. CONCLUSIONS: Together, these data identify miR-6868-5p as a novel determinant of FOXM1 expression and establish a miR-6868-5p/FOXM1 regulatory circuit for CRC angiogenesis, providing potential target for CRC treatment.

An integrated bioinformatical analysis to evaluate the role of KIF4A as a prognostic biomarker for breast cancer.

PURPOSE: The aim of this study was to investigate the diagnostic and prognostic value of human kinesin family member 4A (KIF4A) as an effective biomarker for breast cancer. MATERIALS AND METHODS: Cancer Genome Atlas data and 12 independent public breast cancer microarray data sets were downloaded and analyzed using individual and pooled approaches. RESULTS: The results of our study revealed a strong and positive correlation between KIF4A expression and malignant features of breast cancer. KIF4A had a strong prognostic value in both ER-positive and ER-negative breast cancers comparable to or even better than tumor size, lymph node invasion, and Elston grade. We also found that KIF4A might be the target gene of microRNA-335, which can suppress KIF4A expression by targeting the 3'-untranslated region of its mRNA. CONCLUSION: KIF4A might serve as a robust prognostic predictor for breast cancer. Targeting KIF4A activity could be a promising therapeutic option in breast cancer treatment.

Ribonucleotide reductase subunit M2B deficiency leads to mitochondrial permeability transition pore opening and is associated with aggressive clinicopathologic manifestations of breast cancer.

Ribonucleotide reductase small subunit M2B (RRM2B) plays an essential role in maintaining mitochondrial homeostasis. Mitochondrial permeability transition pore (MPTP) is a key regulator of mitochondrial homeostasis. MPTP contributes to cell death and is crucial in cancer progression. RRM2B's relation to MPTP is not well known, and the role of RRM2B in cancer progression is controversial. Here, our aim was to study the role of RRM2B in regulating MPTP and the association between RRM2B and clinicopathological manifestations in breast cancer. Analysis of Rrm2b-/- mice cells found changes consistent with MPTP opening, including mitochondrial swelling and upregulation of cyclophilin D (CypD), a protein that activates MPTP opening. Silencing of RRM2B gene expression in MCF7 and KB cell lines led to MPTP opening. Accordingly, dysfunctional oxidative phosphorylation and elevated superoxide levels were also detected in RRM2B-silenced MCF7 and KB cell lines, which was consistent with the findings by gene set enrichment analysis of 159 breast cancer cases that genes involving respiratory electron transport were enriched in high-RRM2B breast cancer, and genes involving biologic oxidation were enriched in low-RRM2B breast cancers. A metabolomic study revealed that spermine levels in RRM2B-silenced MCF7 and KB cells were only 5% and 8% of control levels, respectively. Addition of exogenous spermine to RRM2B-silenced MCF7 and KB cells was able to reverse the MPTP opening induced by RRM2B deficiency. These results suggest that RRM2B may induce MPTP opening through reducing spermine levels. Immunohistochemical analysis of 148 breast cancer cases showed that RRM2B and CypD protein levels were inversely correlated in breast cancer specimens (P<0.05), so were their associated clinicopathologic parameters that high-level RRM2B expression was associated with better clinicopathological features. We conclude that RRM2B deficiency leads to MPTP opening mediated by spermine. Coupling of low RRM2B and high CypD expression is associated with aggressive manifestations of breast cancer.

Risk factors for hypocalcemia and hypoparathyroidism following thyroidectomy: a retrospective Chinese population study.

BACKGROUND: Hypocalcemia is one of the most common postoperative complications following thyroid surgery in clinical practice. The occurrence of hypocalcemia is mainly attributed to hypoparathyroidism when parathyroid glands are devascularized, injured, or dissected during the surgery. The aim of this study was to analyze the risk factors for hypocalcemia and hypoparathyroidism following thyroidectomy. PATIENTS AND METHODS: A total of 278 patients who underwent thyroid surgery were analyzed retrospectively. Univariate analysis and multivariable logistic regression were performed to discover the risk factors for hypocalcemia and hypoparathyroidism. RESULTS: Postoperative hypocalcemia occurred in 76 (27.3%) patients and hypoparathyroidism occurred in 42 (15.1%) patients. Seven factors were significantly related to the presence of postoperative hypocalcemia, namely, age (P=0.049), gender (P=0.015), lateral lymph node dissection (P=0.017), operation type (P<0.001), preoperative parathyroid hormone (PTH) level (P=0.035), operation time (P=0.001), and applying carbon nanoparticles (CNs; P=0.007). Our result revealed that gender (P=0.014), lateral lymph node dissection (P=0.038), operation type (P<0.001), operative time (P<0.001), and applying CNs (P=0.001) had a significant correlation with postoperative hypoparathyroidism. CONCLUSION: These findings were crucial for guiding surgeons to prevent the occurrence of hypocalcemia and hypoparathyroidism.

Inhibition of CXCL12/CXCR4 axis as a potential targeted therapy of advanced gastric carcinoma.

The whole outcome for patients with gastric carcinoma (GC) is very poor because most of them remain metastatic disease during survival even at diagnosis or after surgery. Despite many improvements in multiple strategies of chemotherapy, immunotherapy, and targeted therapy, exploration of novel alternative therapeutic targets is still warranted. Chemokine receptor 4 (CXCR4) and its chemokine ligand 12 (CXCL12) have been identified with significantly elevated levels in various malignancies including GC, which correlates with the survival, proliferation, angiogenesis, and metastasis of tumor cells. Increasing experimental evidence suggests an implication of inhibition of CXCL12/CXCR4 axis as a promising targeted therapy, although there are rare trials focused on the therapeutic efficacy of CXCR4 inhibitors in GC until recently. Therefore, it is reasonable to infer that specific antagonists or antibodies targeting CXCL12/CXCR4 axis alone or combined with chemotherapy will be effective and worthy of further translational studies as a potential treatment strategy in advanced GC.

Human mitochondrial pyrroline-5-carboxylate reductase 1 promotes invasiveness and impacts survival in breast cancers.

Human mitochondrial pyrroline-5-carboxylate reductase (PYCR) is a house-keeping enzyme that catalyzes the reduction of Δ1-pyrroline-5-carboxylate to proline. This enzymatic cycle plays pivotal roles in amino acid metabolism, intracellular redox potential and mitochondrial integrity. Here, we hypothesize that PYCR1 might be a novel prognostic biomarker and therapeutic target for breast cancer. In this study, breast cancer tissue samples were obtained from Zhejiang University (ZJU set). Immunohistochemistry analysis was performed to detect the protein level of PYCR1, and Kaplan-Meier and Cox proportional analyses were employed in this outcome study. The prognostic significance and performance of PYCR1 mRNA were validated on 13 worldwide independent microarray data sets, composed of 2500 assessable breast cancer cases. Our findings revealed that both PYCR1 mRNA and protein expression were significantly associated with tumor size, grade and invasive molecular subtypes of breast cancers. Independent and pooled analyses verified that higher PYCR1 mRNA levels were significantly associated with poor survival of breast cancer patients, regardless of estrogen receptor (ER) status. For in vitro studies, inhibition of PYCR1 by small-hairpin RNA significantly reduced the growth and invasion capabilities of the cells, while enhancing the cytotoxicity of doxorubicin in breast cancer cell lines MCF-7 (ER positive) and MDA-MB-231 (ER negative). Further population study also validated that chemotherapy significantly improved survival in early-stage breast cancer patients with low PYCR1 expression levels. Therefore, PYCR1 might serve as a prognostic biomaker for either ER-positive or ER-negative breast cancer subtypes and can also be a potential target for breast cancer therapy.

Rare Gingival Metastasis by Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) uncommonly metastasizes to the gingiva, which always means a poor outcome. We reported a rare HCC case with multiple metastases to gingiva, lungs, and brain. A 60-year-old man was initially diagnosed as HCC with metastases to double lungs. He was subjected to a transarterial chemoembolization (TACE) (5-fluorouracil, 750 mg) and two cycles of intravenous chemotherapy (gemcitabine 1.8 g at days 1 and 8, oxaliplatin 200 mg at day 2, every 4 weeks). However, the volume of liver tumor still increased. A bean-size gingival nodule growing with occasional bleeding was also found. TACE (5-fluorouracil 750 mg, perarubicin 40 mg, cisplatin 20 mg) was performed again and an oral sorafenib therapy (400 mg, twice per day) was adopted. The disease maintained relatively stable for about 6 months until a second obvious progress. The gingival nodule was then palliatively excised and identified as a poorly differentiated metastatic HCC by histopathological examination. Best supportive treatments were made since the performance score was too bad. Finally, cerebral metastases occurred and the patient died of systemic failure. Upon review of previous reports, we discussed risk factors, clinical and pathological characteristics, treatments, and prognosis of gingival metastasis by HCC.

FOXM1 evokes 5-fluorouracil resistance in colorectal cancer depending on ABCC10.

5-Fluorouracil (5-FU) is the most commonly used chemotherapeutic agent for colorectal cancer (CRC). However, frequently occurred 5-FU resistance poses a great challenge in the clinic. Elucidating the underlying mechanisms and developing effective strategies against 5-FU resistance are highly desired. Here we identified the upregulation of FOXM1 in 5-FU nonresponsive CRC patients by gene expression profile analysis and 5-FU-resistant CRC cells by qRT-PCR assay. Silencing of FOXM1 promoted the sensitivity of CRC cells to 5-FU by enhancing cell apoptosis, while overexpression of FOXM1 conferred CRC cells with 5-FU resistance both in vitro and in vivo. Furthermore, we showed that genetic and pharmacological inhibition of FOXM1 resensitized resistant CRC cells to 5-FU treatment. Mechanistically, FOXM1 promoted the transcription of ABCC10 by directly binding to its promoter region. Notably, treatment with ABCC10 inhibitor reversed FOXM1-induced resistance to 5-FU in vivo. Clinical investigation revealed that the levels of FOXM1 and ABCC10 were positively correlated in CRC tissues. Therefore, FOXM1 promotes 5-FU resistance by upregulating ABCC10, suggesting that FOXM1/ABCC10 axis may serve as a potential therapeutic target for 5-FU resistance in CRC patients.