Treatment Outcome of Different Chemotherapy in Patients With Relapsed or Metastatic Malignant Urachal Tumor.

BACKGROUND: Malignant urachal tumor is a rare subtype of genitourinary cancer. Our aim was to explore the optimal chemotherapy regimens for relapsed or metastatic urachal carcinoma. MATERIALS AND METHODS: We retrospectively enrolled 24 adult patients with relapsed or metastatic urachal carcinoma from January 2014 to September 2020 at Sun Yat-sen University Cancer Center. We summarized the chemotherapy regimens and classified them as fluorouracil based, platinum based, and paclitaxel based. Nine patients received XELOX (capecitabine and oxaliplatin) regimens, seven patients received TX (paclitaxel and capecitabine) regimens, and eight of them received chemotherapy including GP (gemcitabine and cisplatin), TP (paclitaxel and cisplatin), TN (paclitaxel and nedaplatin), and tislelizumab. RESULTS: The disease control rate was 75%. Among all patients, one patient treated with XELOX achieved partial remission (PR), while 17 patients showed stable disease. The median progression-free survival (PFS) and overall survival (OS) in all treated patients was 7.43 and 29.7 months, respectively. The patients receiving first-line platinum-based chemotherapy presented better PFS than those without platinum (median PFS 8.23 vs. 3.80 months, p = 0.032), but not significant for OS between two groups. There is no significant difference in PFS and OS for fluorouracil-based and paclitaxel-based groups as first-line regimen. Next-generation gene sequencing revealed TP53 mutation and low tumor mutational burden in five out of seven cases. CONCLUSION: The platinum-based chemotherapy regimen is effective for relapsed or metastatic urachal carcinoma.

Circular RNA circSNX6 promotes sunitinib resistance in renal cell carcinoma through the miR-1184/GPCPD1/ lysophosphatidic acid axis.

Sunitinib resistance is a major challenge in systemic therapy for renal cell carcinoma (RCC). The role of circular RNAs (circRNAs) in regulating sunitinib resistance of RCC is largely unknown. We established sunitinib-resistant RCC cell lines in vivo. Through RNA-sequencing, we identified circSNX6, whose expression is upregulated in sunitinib-resistant cells compared with their parental cells. High circSNX6 expression was correlated with sunitinib resistance and worse oncologic outcomes in a cohort of 81 RCC patients. In vitro and in vivo experiments confirmed that circSNX6 could promote sunitinib resistance in RCC. circSNX6 acts as a molecular "sponge" to relieve the suppressive effect of microRNA (miR)-1184 on its target gene, glycerophosphocholine phosphodiesterase 1 (GPCPD1), which increases intracellular lysophosphatidic acid (LPA) levels and, ultimately, promotes sunitinib resistance in RCC cells. Our findings demonstrated that the circSNX6/miR-1184/GPCPD1 axis had a critical role in regulation of intracellular LPA levels and sunitinib resistance in RCC; they also provide a novel prognostic indicator and promising therapeutic targets.

Cordycepin enhances the chemosensitivity of esophageal cancer cells to cisplatin by inducing the activation of AMPK and suppressing the AKT signaling pathway.

Although cisplatin (cDDP), is a first-line chemotherapy drug for esophageal cancer, it still has the potential to develop drug resistance and side effects. There is increasing evidence that cordycepin can work synergistically with other chemotherapy drugs. Therefore, we investigated whether combination therapy of cordycepin and cDDP may enhance the therapeutic effect of cDDP. We performed a series of functional tests to study the effect of medical treatment on esophageal cancer cells. We then used GO analysis to examine the pathways affected by treatment with cordycepin and cDDP. Next, we observed changes in the abundance of the selected pathway proteins. The in vivo animal model supported the results of the in vitro experiments. Co-treatment with cordycepin and cDDP inhibited cell growth, migration, and metastasis, as well as induced apoptosis. Cordycepin was found to effectively enhance activation of AMPK and inhibited activity of AKT. In all treatment groups, the expression levels of p-PI3K, p-Akt, p-p70S6K, Caspase-3, and Bcl-2 were significantly reduced, while the expression levels of p-AMPK, cleaved Caspase-3, and Bax increased, and the total levels of Akt, PI3K, and p70S6K levels remained unchanged. Overall, cordycepin was found to enhance the chemical sensitivity of esophageal cancer cells to cisplatin by inducing AMPK activation and inhibiting the AKT signaling pathway. Combination therapy of cordycepin and cisplatin represent a novel potential treatment of esophageal cancer.

A positive feedback loop consisting of C12orf59/NF-κB/CDH11 promotes gastric cancer invasion and metastasis.

BACKGROUND: Metastasis remains the main cause of cancer-related death for gastric cancer (GC) patients, but the mechanisms are poorly understood. Using The Cancer Genome Atlas (TCGA) data base and bioinformatics analyses, we identified C12orf59 might act as a potential oncogenic protein in GC. METHODS: We investigate the expression pattern and clinical significance of C12orf59 in two independent cohorts of GC samples. In the training cohort, we used the X-tile program software to generate the optimal cutoff value for C12orf59 expression in order to classify patients accurately according to clinical outcome. In the validation cohort, this derived cutoff score was applied to exam the association of C12orf59 expression with survival outcome. A series of in vivo and in vitro assays were then performed to investigate the function of C12orf59 in GC. RESULTS: C12orf59 was significantly upregulated, and associated with poor survival outcome in two cohorts of GC samples. Gain- and loss of- function studies demonstrated C12orf59 promotes GC cell invasive and metastatic capacity both in vitro and in vivo, and induces epithelial-mesenchymal transition and angiogenesis. Mechanically, C12orf59 exerts oncogenic functions by up-regulating CDH11 expression via NF-κB signaling. Interesting, CDH11 could in turn promote NF-κB bind to C12orf59's promoter and form a positive feedback loop to sustain the metastatic ability of GC cells. Additionally, downregulation of miR-654-5p is another important mechanism for C12orf59 overexpression in GC. CONCLUSION: Our finding suggested the newly identified C12orf59/NF-κB/CDH11 feedback loop may represent a new strategy for GC treatment.

LINC01410-miR-532-NCF2-NF-kB feedback loop promotes gastric cancer angiogenesis and metastasis.

Dysregulation of non-coding RNAs, including miRNAs and lncRNAs has been reported to play vital roles in gastric cancer (GC) carcinogenesis, but the mechanism involved is largely unknown. Using the cancer genome atlas (TCGA) data set and bioinformatics analyses, we identified miR-532-5p as a potential tumor suppressor in GC, and found that lncRNA LINC01410 might be a negative regulator of miR-532-5p. We then conducted a series of in vivo and in vitro assays to explore the effect of LINC01410 on miR-532-5p-mediated GC malignancy and the underlying mechanism involved. MiR-532-5p overexpression inhibited GC metastasis and angiogenesis in vitro and in vivo, whereas miR-532-5p silencing had the opposite effect. Further study showed that miR-532-5p attenuated NF-κB signaling by directly inhibiting NCF2 expression, while miR-532-5p silencing in GC enhanced NF-κB activity. Furthermore, we demonstrated miR-532-5p down-regulation was caused by aberrantly high expression of LINC01410 in GC. Mechanistically, overexpression of LINC01410 promoted GC angiogenesis and metastasis by binding to and suppressing miR-532-5p, which resulted in up-regulation of NCF2 and sustained NF-κB pathway activation. Interestingly, NCF2 could in turn increase the promoter activity and expression of LINC01410 via NF-κB, thus forming a positive feedback loop that drives the malignant behavior of GC. Finally, high expression of LINC01410, along with low expression of miR-532-5p, was associated with poor survival outcome in GC patients. Our studies uncover a mechanism for constitutive LINC1410-miR-532-5p-NCF2-NF-κB feedback loop activation in GC, and consequently, as a potential therapeutic target in GC treatment.

Decreased expression of miR-939 contributes to chemoresistance and metastasis of gastric cancer via dysregulation of SLC34A2 and Raf/MEK/ERK pathway.

BACKGROUND: The development of chemoresistance and metastasis are the leading causes of death for gastric cancer (GC) patients, however, the molecular mechanisms involved remain unclear. Dysregulation of miRNAs is associated with a variety of disease, including GC. Recently, microarray profiling analysis revealed that miR-939 was dysregulated in human GC samples, but the role of miR-939 in GC has not been intensively investigated. METHODS: In the present study, we firstly examined the expression pattern of miR-939 in two independent cohorts of clinical GC samples: one cohort of 112 GC patients with stage I-III disease who underwent surgery followed by adjuvant chemotherapy; and another cohort of 110 GC patients with stage IV disease who received palliative chemotherapy. A series of in vivo and in vitro assays were then performed to investigate the function of miR-939 in GC. RESULTS: We detected that reduced expression of miR-939 was associated with chemoresistance and increased risk of tumor recurrence in GC patients. Further function study demonstrated that overexpression of miR-939 suppressed GC cell growth, and enhanced 5-fluorouracil-induced chemosensitivity by compromising cellular growth and inducing apoptosis in vitro and in vivo. Moreover, miR-939 repressed the migration and invasion of GC cells in vitro, and diminished the occurrence of lung metastasis in vivo. We further identified solute carrier family 34 member 2 (SLC34A2) was a novel target of miR-939. Mechanistically, we elucidated that miR-939 exerted its function mainly through inhibiting SLC34A2/Raf/MEK/ERK pathway, which is activated in GC. Multivariate analysis identified miR-939, SLC34A2, and their combination as independent indicators for poor prognosis and tumor recurrence in GC patients. CONCLUSION: Our data indicate that miR-939 acts as a tumor suppressor miRNA in GC, and miR-939/SLC34A2 axis represents a novel therapeutic strategy for future GC treatment.

ULK1: a promising biomarker in predicting poor prognosis and therapeutic response in human nasopharygeal carcinoma.

Plenty of studies have established that dysregulation of autophagy plays an essential role in cancer progression. The autophagy-related proteins have been reported to be closely associated with human cancer patients' prognosis. We explored the expression dynamics and prognostic value of autophagy-related protein ULK1 by immunochemistry (IHC) method in two independent cohorts of nasopharygeal carcinoma (NPC) cases. The X-tile program was applied to determine the optimal cut-off value in the training cohort. This derived cutoff value was then subjected to analysis the association of ULK1 expression with patients' clinical characteristics and survival outcome in the validation cohort and overall cases. High ULK1 expression was closely associated with aggressive clinical feature of NPC patients. Furthermore, high expression of ULK1 was observed more frequently in therapeutic resistant group than that in therapeutic effective group. Our univariate and multivariate analysis also showed that higher ULK1 expression predicted inferior disease-specific survival (DSS) (P<0.05). Consequently, a new clinicopathologic prognostic model with 3 poor prognostic factors (ie, ULK1 expression, overall clinical stage and therapeutic response) could significantly stratify risk (low, intermediate and high) for DSS in NPC patients (P<0.001). These findings provide evidence that, the examination of ULK1 expression by IHC method, could serve as an effective additional tool for predicting therapeutic response and patients' survival outcome in NPC patients.

XRCC1 and ADPRT polymorphisms associated with survival in breast cancer cases treated with chemotherapy.

AIM: To investigate whether XRCC1 and ADPRT polymorphisms might be associated with outcomes of breast cancer. METHODS: A prospective study was conducted with a total of 335 breast cancer patients undergoing chemotherapy consecutively collected from Jan. 2005 to Jan. 2008. Genotyping of XRCC1 and ADPRT polymorphisms was conducted by PCR-RFLP assay. RESULTS: All 335 patients were followed up until death or the end of Jan. 2012, with a median follow-up period of 38.8 (2-64) months. It was shown that the variant genotype of XRCC1 399Gln/Gln was strongly significantly associated with a decreased risk of death from breast cancer, with an HR (95% CI) of 0.52 (0.28-0.91). Similarly, individuals carrying the ADPRT 762Ala/Ala demonstrated longer survival compared to ADPRT 762 Val/ Val, with an HR (95% CI) of 0.58 (0.31-0.97). Individuals with combination genotypes of XRCC1 399Gln allele and ADPRT 762Ala/Ala presented with a longer survival, the HR (95% CI) being 0.56 (0.32-0.97). CONCLUSION: We found a significant association between XRCC1399Gln/ Gln and ADPRT 762Ala/Ala polymorphisms and clinical outcomes. These two genotypes could be used as a surrogate markers of clinical outcome in glioma cases receiving chemotherapy.