BACKGROUND Recently, long noncoding RNAs (lncRNAs) have received wide attention in the area of tumor progression. Dysregulation of lncRNAs has been shown to participated in colon cancer, a known malignant tumor. This study aimed to identify the way lncRNA PVT1 affects the progression of colon cancer. MATERIAL AND METHODS Both human colon cancer tissues and 30 paired adjacent normal tissue samples, as well as the colon cancer cells, were collected. Then quantitative real-time (qRT-PCR) was performed to detect the expression of lncRNA PVT1 and miR-26b. Furthermore, the role of PVT1 was determined by function assays such as cell proliferation assay, invasion assay, and wound healing assay. The mechanism was studied using western blot assay and luciferase assay. RESULTS We demonstrate that the expression of PVT1 was significantly higher in tumor tissue compared with the adjacent normal tissue with a lower expression of miR-26b. Moreover, PVT1 promoted tumor growth, migration, and invasion in vitro. In addition, further experiments revealed that miR-26b was a direct target of PVT1 and could inhibit cell migration, invasion, and proliferation in colon cancer. CONCLUSIONS Our results suggest that PVT1 could promote metastasis and proliferation of colon cancer via endogenous sponging and inhibiting the expression of miR-26b, which may highlight the significance of lncRNA PVT1 in colon cancer tumorigenesis.

The unfolded protein response (UPR) signal in tumor cells activates UPR signaling in neighboring macrophages, which leads to tumor-promoting inflammation by up-regulating UPR target genes and proinflammatory cytokines. However, the molecular basis of this endoplasmic reticulum (ER) stress transmission remains largely unclear. Here, we identified the secreted form of Golgi protein 73 (GP73), a Golgi-associated protein functional critical for hepatocellular carcinoma (HCC) growth and metastasis, is indispensable for ER stress transmission. Notably, ER stressors increased the cellular secretion of GP73. Through GRP78, the secreted GP73 stimulated ER stress activation in neighboring macrophages, which then released cytokines and chemokines involved in the tumor-associated macrophage (TAM) phenotype. Analysis of HCC patients revealed a positive correlation of GP73 with glucose-regulated protein 78 (GRP78) expression and TAM density. High GP73 and CD206 expression was associated with poor prognosis. Blockade of GP73 decreased the density of TAMs, inhibited tumor growth, and prolonged survival in two mouse HCC models. Conclusion: Our findings provide insight into the molecular mechanisms of extracellular GP73 in the amplification and transmission of ER stress signals.

Viral infection triggers the formation of mitochondrial antiviral signaling protein (MAVS) aggregates, which potently promote immune signaling. Autophagy plays an important role in controlling MAVS-mediated antiviral signaling; however, the exact molecular mechanism underlying the targeted autophagic degradation of MAVS remains unclear. Here, we investigated the mechanism by which RNF34 regulates immunity and mitophagy by targeting MAVS RNF34 binds to MAVS in the mitochondrial compartment after viral infection and negatively regulates RIG-I-like receptor (RLR)-mediated antiviral immunity. Moreover, RNF34 catalyzes the K27-/K29-linked ubiquitination of MAVS at Lys 297, 311, 348, and 362 Arg, which serves as a recognition signal for NDP52-dependent autophagic degradation. Specifically, RNF34 initiates the K63- to K27-linked ubiquitination transition on MAVS primarily at Lys 311, which facilitates the autophagic degradation of MAVS upon RIG-I stimulation. Notably, RNF34 is required for the clearance of damaged mitochondria upon viral infection. Thus, we elucidated the mechanism by which RNF34-mediated autophagic degradation of MAVS regulates the innate immune response, mitochondrial homeostasis, and infection.

Background/Aims: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an ideal anti-tumor drug because it exhibits selective cytotoxicity against cancer cells. However, certain cancer cells are resistant to TRAIL, and the potential mechanisms are still unclear. The aim of this study was to reduce the resistance of colorectal cancer (CRC) cells to TRAIL. Methods: Quantitative real-time PCR analysis was performed to detect the expression of microRNA-128 (miR-128) in tissues from patients with CRC and CRC cell lines. MTT assays were used to evaluate the effect of miR-128 on TRAIL-induced cytotoxicity against CRC cell lines. The distribution of death receptor 5 (DR5) and the production of reactive oxygen species (ROS) were detected by flow cytometry analysis. Western blot, flow cytometry, and luciferase reporter assays were performed to evaluate the potential mechanism and pathway of miR-128-promoted apoptosis in TRAIL-treated CRC cells. Results: MiR-128 expression was downregulated in tumor tissues from patients with CRC as well as in CRC cell lines in vitro. The enforced expression of miR-128 sensitized CRC cells to TRAIL-induced cytotoxicity by inducing apoptosis. Mechanistically, bioinformatics, western blot analysis, and luciferase reporter assays showed that miR-128 directly targeted sirtuin 1 (SIRT1) in CRC cells. miR-128 overexpression suppressed SIRT1 expression, which promoted the production of ROS in TRAIL-treated CRC cells. This increase of ROS subsequently induced DR5 expression, and thus increased TRAIL-induced apoptosis in CRC cells. Conclusion: The combination of miR-128 with TRAIL may represent a novel approach for the treatment of CRC.

Current studies have highlighted long non-coding RNAs (lncRNAs) as critical regulators in various cancers, including colorectal cancer (CRC). By utilizing publicly available data from The Cancer Genome Atlas dataset, MLK7 antisense RNA 1 (MLK7-AS1) was identified as a novel lncRNA that correlated with CRC progression. The results of reverse transcription-quantitative polymerase chain reaction (RT-qPCR) revealed a significant upregulation of MLK7-AS1 in both CRC tissue samples and cell lines. In addition, a positive correlation was observed between increased MLK7-AS1 expression and several clinicopathological factors in patients with CRC. Importantly, MLK7-AS1 knockdown suppressed CRC cell proliferation and promoted G1/G0 phase arrest and apoptosis in vitro, whereas MLK7-AS1 overexpression exhibited opposite effects. Consistently, decreased MLK7-AS1 expression inhibited tumor growth in vivo. Furthermore, RT-qPCR and western blot assays revealed that p21 may be a potential downstream target of MLK7-AS1. To the best of the authors' knowledge, this is the first study to report that MLK7-AS1 has potential as a biomarker and may promote proliferation in CRC partially through downregulating p21 expression.

Background/Aims: Doxorubicin (DOX) is a widely used chemotherapeutic agent for colorectal cancer (CRC). However, the acquirement of DOX resistance limits its clinical application for cancer therapy. Mounting evidence has suggested that aberrantly expressed lncRNAs contribute to drug resistance of various tumors. Our study aimed to explore the role and molecular mechanisms of lncRNA X-inactive specific transcript (XIST) in chemoresistance of CRC to DOX. Methods: The expressions of XIST, miR-124, serum and glucocorticoid-inducible kinase 1 (SGK1) mRNA in DOX-resistant CRC tissues and cells were detected by qRT-PCR or western blot analysis. DOX sensitivity was assessed by detecting IC50 value of DOX, the protein levels of P-glycoprotein (P-gp) and glutathione S-transferase-π (GST-π) and apoptosis. The interactions between XIST, miR-124 and SGK1 were confirmed by luciferase reporter assay, qRT-PCR and western blot. Xenograft tumor assay was used to verify the role of XIST in DOX resistance in CRC in vivo. Results: XIST expression was upregulated and miR-124 expression was downregulated in DOX-resistant CRC tissues and cells. Knockdown of XIST inhibited DOX resistance of CRC cells, as evidenced by the reduced IC50 value of DOX, decreased P-gp and GST-π levels and enhanced apoptosis in XIST-silenced DOX-resistant CRC cells. Additionally, XIST positively regulated SGK1 expression by interacting with miR-124 in DOX-resistant CRC cells. miR-124 suppression strikingly reversed XIST-knockdown-mediated repression on DOX resistance in DOX-resistant CRC cells. Moreover, SGK1-depletion-elicited decrease of DOX resistance was greatly restored by XIST overexpression or miR-124 inhibition in DOX-resistant CRC cells. Furthermore, XIST knockdown enhanced the anti-tumor effect of DOX in CRC in vivo. Conclusion: XIST exerted regulatory function in resistance of DOX possibly through miR-124/SGK1 axis, shedding new light on developing promising therapeutic strategy to overcome chemoresistance in CRC patients.

Objective To investigate the expression and clinical significance of vascular endothelial growth factor (VEGF) and its receptor Flk-1 in nephroblastoma. To assess whether tumor microvessel density (MVD) immunoreactivity, determined by the CD34 antigen, is related to the expression of VEGF and Flt-1. Methods Immunohistochemical staining (SABC) was used to examine MVD and the expression of VEGF, Flk-1 in 33 nephroblastoma tissues, 33 paracancer renal tissues and 6 normal kidney tissues. The relation between the expressions of VEGF, Flk-1 and MVD was analyzed in different clinical stage and pathology type, Patients were treated preoperatively with chemotherapy and mean follow up was 34 months. Results The positive rates of VEGF and Flk-1 in nephroblastoma tissues were 81.8% and 69.7%, the positive rates of VEGF and Flk-1 in paracancer renal tissues were 9.1% and 6.1%, the expressions of VEGF and Flk-1 were negative in all normal kidney. The differences between the three groups were statistically significant (P＜0.05). In nephroblastoma tissues,the expression of VEGF correlated to both Flt-1 and MVD (P＜0.05), and the expression of Flt-1 correlated to MVD (P＜0.05). In addition, the expressions of VEGF and Flk-1 were increased in clinical stage Ⅲ and poor prognosis. Conclusions These results indicate that VEGF and Flk-1 may play an important role in nephroblastoma angiogenesis. Increased expression of VEGF and Flk-1 in nephroblastoma correlated with tumor stage, clinical progression and tumor related death. VEGF and Flk-1 protein expression are closely related to MVD and seem to be a important predictor for poor prognosis in treated patients with nephroblastoma.

OBJECTIVE:To investigate the significance of telomerase activity in urine in the diagnosis and recurrence surveillance of urothelial carcinoma.METHODS:Telomerase activity in urine of 54 cases of urothelial carcinoma (urothelial carcinoma group) was estimated by polymerase chain reaction-enzyme-linked immunosorbent assay, and monitored continuously in 23 cases after tumor removal. 46 patients with benign urological diseases were also included as the control group.RESULTS:The telomerase activity in urine of patients with urothelial carcinoma increased significantly as compared with the control group (P < 0.001), decreased into the normal range after tumor removal, and rose again upon intravesical tumor recurrence before the screening of recurrent tumors by cystoscopy. The higher the grade of tumor, the higher the telomerase activity; no correlation could be found between the preoperative level of telomerase activity in urine and recurrence.CONCLUSIONS:The examination of telomerase activity in urine is helpful in the diagnosis of urothelial carcinoma and may be related to the differentiation degree of tumors. Its sensitivity is higher than that of cystoscopic examination and may become an important ancillary method in the screening of urothelial carcinoma recurrence.