Search

Sustaining DNA damage response (DDR) signalling via retention of DDR factors at damaged sites is important for transmitting damage-sensing and repair signals. Herein, we found that DNA damage provoked the association of ribosomes with IRES region in lncRNA CTBP1-DT, which overcame the negative effect of upstream open reading frames (uORFs), and elicited the novel microprotein DNA damage-upregulated protein (DDUP) translation via a cap-independent translation mechanism. Activated ATR kinase-mediated phosphorylation of DDUP induced a drastic ‘dense-to-loose’ conformational change, which sustained the RAD18/RAD51C and RAD18/PCNA complex at damaged sites and initiated RAD51C-mediated homologous recombination and PCNA-mediated post-replication repair mechanisms. Importantly, treatment with ATR inhibitor abolished the effect of DDUP on chromatin retention of RAD51C and PCNA, thereby leading to hypersensitivity of cancer cells to DNA-damaging chemotherapeutics. Taken together, our results uncover a plausible mechanism underlying the DDR sustaining and might represent an attractive therapeutic strategy in improvement of DNA damage-based anticancer therapies.

Mitochondrial dynamics play vital roles in the tumorigenicity and malignancy of various types of cancers by promoting the tumor-initiating potential of cancer cells, suggesting that targeting crucial factors that drive mitochondrial dynamics may lead to promising anticancer therapies. In the current study, we report that overexpression of mitochondrial fission factor (MFF), which is upregulated significantly in liver cancer–initiating cells (LCIC), promotes mitochondrial fission and enhances stemness and tumor-initiating capability in non-LCICs. MFF-induced mitochondrial fission evoked mitophagy and asymmetric stem cell division and promoted a metabolic shift from oxidative phosphorylation to glycolysis that decreased mitochondrial reactive oxygen species (ROS) production, which prevented ROS-mediated degradation of the pluripotency transcription factor OCT4. CRISPR affinity purification in situ of regulatory elements showed that T-box transcription factor 19 (TBX19), which is overexpressed uniquely in LCICs compared with non-LCICs and liver progenitor cells, forms a complex with PRMT1 on the MFF promoter in LCICs, eliciting epigenetic histone H4R3me2a/H3K9ac-mediated transactivation of MFF. Targeting PRMT1 using furamidine, a selective pharmacologic inhibitor, suppressed TBX19-induced mitochondrial fission, leading to a profound loss of self-renewal potential and tumor-initiating capacity of LCICs. These findings unveil a novel mechanism underlying mitochondrial fission–mediated cancer stemness and suggest that regulation of mitochondrial fission via inhibition of PRMT1 may be an attractive therapeutic option for liver cancer treatment.Significance:These findings show that TBX19/PRMT1 complex–mediated upregulation of MFF promotes mitochondrial fission and tumor-initiating capacity in liver cancer cells, identifying PRMT1 as a viable therapeutic target in liver cancer.

This document contains Supplemental Materials and Methods and Supplementary Data

Mitochondrial dynamics play vital roles in the tumorigenicity and malignancy of various types of cancers by promoting the tumor-initiating potential of cancer cells, suggesting that targeting crucial factors that drive mitochondrial dynamics may lead to promising anticancer therapies. In the current study, we report that overexpression of mitochondrial fission factor (MFF), which is upregulated significantly in liver cancer–initiating cells (LCIC), promotes mitochondrial fission and enhances stemness and tumor-initiating capability in non-LCICs. MFF-induced mitochondrial fission evoked mitophagy and asymmetric stem cell division and promoted a metabolic shift from oxidative phosphorylation to glycolysis that decreased mitochondrial reactive oxygen species (ROS) production, which prevented ROS-mediated degradation of the pluripotency transcription factor OCT4. CRISPR affinity purification in situ of regulatory elements showed that T-box transcription factor 19 (TBX19), which is overexpressed uniquely in LCICs compared with non-LCICs and liver progenitor cells, forms a complex with PRMT1 on the MFF promoter in LCICs, eliciting epigenetic histone H4R3me2a/H3K9ac-mediated transactivation of MFF. Targeting PRMT1 using furamidine, a selective pharmacologic inhibitor, suppressed TBX19-induced mitochondrial fission, leading to a profound loss of self-renewal potential and tumor-initiating capacity of LCICs. These findings unveil a novel mechanism underlying mitochondrial fission–mediated cancer stemness and suggest that regulation of mitochondrial fission via inhibition of PRMT1 may be an attractive therapeutic option for liver cancer treatment. Significance: These findings show that TBX19/PRMT1 complex–mediated upregulation of MFF promotes mitochondrial fission and tumor-initiating capacity in liver cancer cells, identifying PRMT1 as a viable therapeutic target in liver cancer.

Background Radiotherapy is a conventional and effective local treatment for breast cancer. However, residual or recurrent tumors appears frequently because of radioresistance. Novel predictive marker and the potential therapeutic targets of breast cancer radioresistance needs to be investigated. Methods In this study, we screened all 10 asparagine-linked glycosylation (ALG) members in breast cancer patients’ samples by RT-PCR. Cell viability after irradiation (IR) was determined by CCK-8 assay and flow cytometry. The radiosensitivity of cell lines with different ALG3 expression was determined with the colony formation assay by fitting the multi-target single hit model to the surviving fractions. Cancer stem-like traits were assessed by RT-PCR, Western blot, and flow cytometry. The mechanisms of ALG3 influencing radiosensitivity was detected by Western blot and immunoprecipitation. And the effect of ALG3 on tumor growth after IR was verified in an orthotopic xenograft tumor models. The association of ALG3 with prognosis of breast cancer patients was confirmed by immunohistochemistry. Results ALG3 was the most significantly overexpressing gene among ALG family in radioresistant breast cancer tissue. Overexpression of ALG3 predicted poor clinicopathological characteristics and overall survival (OS), and early local recurrence-free survival (LRFS) in breast cancer patients. Upregulating ALG3 enhanced radioresistance and cancer stemness in vitro and in vivo. Conversely, silencing ALG3 increased the radiosensitivity and repressed cancer stemness in vitro, and more importantly inhibition of ALG3 effectively increased the radiosensitivity of breast cancer cells in vivo. Mechanistically, our results further revealed ALG3 promoted radioresistance and cancer stemness by inducing glycosylation of TGF-β receptor II (TGFBR2). Importantly, both attenuation of glycosylation using tunicamycin and inhibition of TGFBR2 using LY2109761 differentially abrogated the stimulatory effect of ALG3 overexpression on cancer stemness and radioresistance. Finally, our findings showed that radiation played an important role in preventing early recurrence in breast cancer patients with low ALG3 levels, but it had limited efficacy in ALG3-overexpressing breast cancer patients. Conclusion Our results suggest that ALG3 may serve as a potential radiosensitive marker, and an effective target to decrease radioresistance by regulating glycosylation of TGFBR2 in breast cancer. For patients with low ALG3 levels, radiation remains an effective mainstay therapy to prevent early recurrence in breast cancer.

Serine/Arginine-Rich Splicing Factor 7 (SRSF7), which is previously recognized as a splicing factor, has been revealed to play oncogenic roles in multiple cancers. However, the mechanisms underlying its oncogenic roles have not been well addressed. Here, based on N6-methyladenosine (m6A) co-methylation network analysis across diverse cell lines, we found SRSF7 positively correlated with glioblastoma cell-specific m6A methylation. We then proved SRSF7 is a novel m6A regulator that specifically facilitates the m6A methylation near its binding sites on the mRNAs involved in cell proliferation and migration through recruiting methyltransferase complex. Moreover, SRSF7 promotes the proliferation and migration of glioblastoma cells largely dependent on the m6A methyltransferase. The two single-nucleotide m6A sites on PBK are regulated by SRSF7 and partially mediate the effects of SRSF7 on glioblastoma cells through recognition by IGF2BP2. Together, our discovery revealed a novel role of SRSF7 in regulating m6A and timely confirmed the existence and functional importance of RNA binding protein (RBP) mediated specific regulation of m6A.

MicroRNAs (miRs) have been demonstrated to be associated with multiple processes in the development and progression of human malignancies. Previous studies have observed aberrant downregulation of miR‑144 in several types of cancer, including osteosarcoma. However, the function of miR‑144 and the underlying mechanism in osteosarcoma remain to be elucidated. The present study indicated that miR‑144 was markedly downregulated in osteosarcoma tissues and cell lines compared with that in the normal controls. Restoration of miR‑144 significantly inhibited cell proliferation, migration and invasion of MG‑63 osteosarcoma cells. In addition, Rho‑associated coiled‑coil containing protein kinase 1 (ROCK1) was identified as a novel target of miR‑144 in MG‑63 osteosarcoma cells. Furthermore, knockdown of ROCK1 suppressed the proliferation, migration and invasion of MG‑63 osteosarcoma cells to a similar extent to the effects of miR‑144 overexpression. In addition, the mRNA expression of ROCK1 was increased in osteosarcoma tissues and was negatively correlated with the expression of miR‑144. In conclusion, the results of the present study suggested that miR‑144 acts as a tumor suppressor by targeting ROCK1 in osteosarcoma.

Background Breast cancer (BC) has a marked tendency to spread to the bone, resulting in significant skeletal complications and mortality. Recently, circular RNAs (circRNAs) have been reported to contribute to cancer initiation and progression. However, the function and mechanism of circRNAs in BC bone metastasis (BC-BM) remain largely unknown. Methods Bone-metastatic circRNAs were screened using circRNAs deep sequencing and validated using in situ hybridization in BC tissues with or without bone metastasis. The role of circIKBKB in inducing bone pre-metastatic niche formation and bone metastasis was determined using osteoclastogenesis, immunofluorescence and bone resorption pit assays. The mechanism underlying circIKBKB-mediated activation of NF-κB/bone remodeling factors signaling and EIF4A3-induced circIKBKB were investigated using RNA pull-down, luciferase reporter, chromatin isolation by RNA purification and enzyme-linked immunosorbent assays. Results We identified that a novel circRNA, circIKBKB, was upregulated significantly in bone-metastatic BC tissues. Overexpressing circIKBKB enhanced the capability of BC cells to induce formation of bone pre-metastatic niche dramatically by promoting osteoclastogenesis in vivo and in vitro. Mechanically, circIKBKB activated NF-κB pathway via promoting IKKβ-mediated IκBα phosphorylation, inhibiting IκBα feedback loop and facilitating NF-κB to the promoters of multiple bone remodeling factors. Moreover, EIF4A3, acted acting as a pre-mRNA splicing factor, promoted cyclization of circIKBKB by directly binding to the circIKBKB flanking region. Importantly, treatment with inhibitor eIF4A3-IN-2 reduced circIKBKB expression and inhibited breast cancer bone metastasis effectively. Conclusion We revealed a plausible mechanism for circIKBKB-mediated NF-κB hyperactivation in bone-metastatic BC, which might represent a potential strategy to treat breast cancer bone metastasis.

The early recurrence of hepatocellular carcinoma (HCC) is the main obstacle for long-term survival of patients. Wnt/β-catenin signaling has been involved in the development and progression of HCC. However, the molecular changes that link Wnt/β-catenin activation and HCC early recurrence remain poorly understood. Here we identified AKIP1 as a binding partner of β-catenin. AKIP1 interacted with and sustained β-catenin in the nuclear by blocking its interaction with adenomatous polyposis coli protein (APC). Moreover, AKIP1 enhanced the protein kinase A catalytic subunit (PKAc)-mediated phosphorylation of β-catenin, leading to recruitment of cyclic AMP response element-binding protein (CBP) and activation of β-catenin downstream transcription. Increased AKIP1 expression was observed in HCC clinical samples and correlated with early recurrence and poor prognosis of HCC. AKIP1 promoted invasion and colony outgrowth in vitro and increased intrahepatic and lung metastasis in vivo. Treatment with a CBP inhibitor ICG-001 effectively inhibited the metastatic progression of HCC tumors that had elevated AKIP1 in both cell line and patient-derived xenograft mouse models. Our findings not only establish AKIP1 as a novel regulator of Wnt/β-catenin signaling as well as HCC early recurrence but also highlight targeting the AKIP1/β-catenin/CBP axis as attractive therapies for combating HCC metastatic relapse.

Additional file 4: Supplementary Figure 4. (A) Analysis of correlation between ALG3 expression and cell cycle related genes based on TCGA database were performed. (B) Cyclin B1, cyclin B2, and CDK4 expression were up-regulated in ALG3-tansduced cells and down-regulated in ALG3-knocked out cells. α-Tubulin was detected as a loading control in Western blot. (C, D) Statistical graphs of secondary sphere formation assay in breast cancer cells were plotted. Each bar represents the mean ± SD of three independent experiments. All data were analyzed by Student’s t-test and one-way ANOVA with Tukey’s multiple comparison test. *P

Additional file 5: Supplementary Figure 5. (A, B) Radioresistance-associated pathways were examined by luciferase assay to find out the most influenced pathway after ALG3-knocked out. Each bar represents the mean ± SD of three independent experiments. All data were analyzed by one-way ANOVA with Tukey’s multiple comparison test. (C) mRNA expression level of several genes that regulated by TGF-β pathway in ALG3-sg cells or cells treated by tunicamycin compared with ALG3 control cells were detected by RT-PCR. GAPDH was detected as a loading control in RT-PCR. (D) Upregulation of ALG3 decreased the apoptosis ratio, whereas inhibition of TGFBR2 increased the apoptosis ratio of ALG3-transduced cells after radiation treatment, which were detected by flow cytometry. (E) Statistical graphs of apoptotic cells proportion in the vector, ALG3-vector +LY2109761(TGFBR2 inhibitor), ALG3-transduced, and ALG3-transduced +LY2109761 cells were plotted. Each bar represents the mean ± SD of three independent experiments. Data were analyzed by Student’s t-test. (F) Upregulation of ALG3 led to increasing the number of spheres, while inhibition of TGFBR2 decreased the number of spheres in ALG3-overexpressing cells, which were detected by secondary sphere assay. Each bar represents the mean ± SD of three independent experiments. Data were analyzed by Student’s t-test. (G) Upregulation of ALG3 led to increasing proportion of the CD44+CD24−subpopulation, whereas inhibition of TGFBR2 decreased proportion of the CD44+CD24− subpopulation in ALG3-transduced cells. Each bar represents the mean ± SD of three independent experiments. All data were analyzed by Student’s t-test. *P

Additional file 9: Table S2. Association of ALG3 expression with TP53 status and tumor type.

Additional file 2: Supplementary Figure 2. (A) ALG3 expression after transduction in MCF-7 and ZR-75-30 cell lines was confirmed by Western blot. (B) Representative images of colony assays, with cells exposed to 0,2,4,6 Gy X ray treatment were as shown. (C) Representative image of local radiation treatment was as shown. (D) Immunohistochemistry image of tumor tissues from ALG3-transduced mice depicts successful upregulation of ALG3. Original magnification, 200x and 400x. scale bar = 50 μm. (E) Immunohistochemistry images showed that tumor tissues from ALG3-transduced mice overexpressing Ki67. Original magnification, 200x and 400x. scale bar = 50 μm. (F) Cleaved caspase-3 activity was performed on tumor tissues from mice. *** P

Additional file 6: Supplementary Figure 6. (A–C) Kaplan–Meier analysis using the public breast cancer data sets showed that the ALG3 overexpression indicates shorter RFS, PPS, and OS. Website, https://kmplot.com/analysis/ . (D, E) Kaplan–Meier analysis showed that ALG3 overexpression indicates shorter RFS and OS in the TCGA database.

Additional file 12: Table S5. The detail information of colony assay in MDA-MB-231 cell line.

Additional file 8: Table S1. Molecular baseline characteristics of patients.

Additional file 7: Supplementary Figure 7. (A-B) LRFS and OS of different tumor type patients, stratified by high and low ALG3 expression, were analyzed by Kaplan-Meier analysis with log-rank test. (C-D) Kaplan–Meier curves of LRFS and OS were plotted to evaluate the predictive value of ALG3 in patients grouped by tumor type and receiving radiotherapy or not. (E) Kaplan–Meier curves of LRFS were plotted to evaluate if radiotherapy contribute to prognosis of patients with ALG3 overexpressing in different tumor type. (F) LRFS and OS of patients with different p53 status, stratified by high and low ALG3 expression, were analyzed by Kaplan-Meier analysis with log-rank test. (G) LRFS of patients with mutational p53 who have received radiotherapy or not, stratified by ALG3 expression was analyzed by Kaplan-Meier analysis with log-rank test. (H) Kaplan–Meier curves of LRFS curves were plotted to evaluate if radiotherapy contribute to prognosis of patients with ALG3 overexpressing or with mutational p53.

The incidence of bone metastases in hepatocellular carcinoma (HCC) has increased prominently over the past decade owing to the prolonged overall survival of HCC patients. However, the mechanisms underlying HCC bone‐metastasis remain largely unknown. In the current study, HCC‐secreted lectin galactoside‐binding soluble 3 (LGALS3) is found to be significantly upregulated and correlates with shorter bone‐metastasis‐free survival of HCC patients. Overexpression of LGALS3 enhances the metastatic capability of HCC cells to bone and induces skeletal‐related events by forming a bone pre‐metastatic niche via promoting osteoclast fusion and podosome formation. Mechanically, ubiquitin ligaseRNF219‐meidated α‐catenin degradation prompts YAP1/β‐catenin complex‐dependent epigenetic modifications of LGALS3 promoter, resulting in LGALS3 upregulation and metastatic bone diseases. Importantly, treatment with verteporfin, a clinical drug for macular degeneration, decreases LGALS3 expression and effectively inhibits skeletal complications of HCC. These findings unveil a plausible role for HCC‐secreted LGALS3 in pre‐metastatic niche and can suggest a promising strategy for clinical intervention in HCC bone‐metastasis., Hepatocellular carcinoma (HCC)‐secreted LGALS3 induces osteolytic bone metastasis (BM) via promoting osteoclast fusion and podosome formation. Mechanistically, RNF219‐mediated α‐catenin degradation results in YAP1/β‐catenin‐dependent epigenetic modifications on LGALS3 promoter, eliciting in LGALS3 upregulation in HCC. Blocking YAP1/β‐catenin complex formation on LGALS3 promoter via verteporfin reduces LGALS3 expression and effectively inhibits HCC bone‐metastasis (HCC‐BM), which represents a potential strategy for HCC‐BM clinical treatment.

The incidence of bone metastases in hepatocellular carcinoma (HCC) has increased prominently over the past decade owing to the prolonged overall survival of HCC patients. However, the mechanisms underlying HCC bone-metastasis remain largely unknown. Herein, we reported that HCC-secreted LGALS3 induced bone metastasis and skeletal-related events by promoting formation of bone pre-metastatic niche. We demonstrated that ubiquitin ligase RNF219-meidated α-catenin degradation prompted YAP1/β-catenin-dependent epigenetic modifications of LGALS3 promoter, resulting in LGALS3 upregulation and metastatic bone diseases. Treatment with Verteporfin, a clinical drug for macular degeneration, decreased LGALS3 expression and effectively inhibited skeletal complications of HCC. These findings unveil a plausible role for HCC-secreted LGALS3 in pre-metastatic niche and could suggest a promising strategy for clinical intervention in HCC bone-metastasis.

Background Resistance to platinum-based chemotherapy is a major cause of therapeutic failure during the treatment of epithelial ovarian cancer (EOC) patients. Our study aims to elucidate the molecular mechanisms by which ZNF711 down regulation promotes CISPLATIN resistance in EOC. Methods ZNF711 expression in 150 EOC specimens was examined using immunohistochemistry. ZNF711 expression and the survival of EOC patients were assessed with a Kaplan-Meier analysis. The effects of ZNF711 expression on CDDP resistance were studied by IC50, Annexin V, and colony formation in vitro, and in an in vivo intra-peritoneal tumor model. The molecular mechanism was determined using a luciferase reporter assay, ChIP assay, CAPTURE approach, and co-IP assay. Findings ZNF711 down-regulation exerts a great impact on CDDP resistance for EOC patients by suppressing SLC31A1 and inhibiting CDDP influx. ZNF711 down-regulation promoted, while ZNF711 overexpression drastically inhibited CDDP resistance, both in vivo and in vitro. Mechanistically, the histone demethylase JHDM2A was recruited to the SLC31A1 promoter by ZNF711 and decreased the H3K9me2 level, resulting in the activation of SLC31A1 transcription and enhancement of CDDP uptake. Importantly, co-treatment with the histone methylation inhibitor, BIX-01294, increased the therapeutic efficacy of CDDP treatment in ZNF711-suppressed EOC cells. Interpretation These findings both verified the clinical importance of ZNF711 in CDDP resistance and provide novel therapeutic regimens for EOC treatment. Funding This work was supported by the Natural Science Foundation of China; Guangzhou Science and Technology Plan Projects; Natural Science Foundation of Guangdong Province; The Fundamental Research Funds for the Central Universities; and China Postdoctoral Science Foundation.

Resistance to tamoxifen is a clinically major challenge in breast cancer treatment. Although downregulation of estrogen receptor‐alpha (ERα) is the dominant mechanism of tamoxifen resistance, the reason for ERα decrease during tamoxifen therapy remains elusive. Herein, we reported that Spalt‐like transcription factor 2 (SALL2) expression was significantly reduced during tamoxifen therapy through transcription profiling analysis of 9 paired primary pre‐tamoxifen‐treated and relapsed tamoxifen‐resistant breast cancer tissues. SALL2 transcriptionally upregulated ESR1 and PTEN through directly binding to the DNA promoters. By contrast, silencing SALL2 induced downregulation of ERα and PTEN and activated the Akt/mTOR signaling, resulting in estrogen‐independent growth and tamoxifen resistance in ERα‐positive breast cancer. Furthermore, hypermethylation of SALL2 promoter was found in tamoxifen‐resistant breast cancer. Importantly, in vivo experiments showed that DNA methyltransferase inhibitor‐mediated SALL2 restoration resensitized tamoxifen‐resistant breast cancer to tamoxifen therapy. These findings shed light on the mechanism of SALL2 in regulation of ER and represent a potential clinical signature that can be used to categorize breast cancer patients who may benefit from co‐therapy with tamoxifen and DNMT inhibitor., Resistance to tamoxifen is a clinically important challenge for breast cancer treatment. This study uncovers a mechanism by which the transcription factor SALL2 regulates ERα, and identifies a subset of breast cancer patients who might benefit from tamoxifen/DNMTs inhibitor co‐therapy.

Osteosarcoma (OS) is the most common malignant tumor of the bone, with a high mortality rate and poor prognosis. Receptor tyrosine kinase-like orphan receptor 2 (ROR2) has been reported to be dysregulated in human malignancies. More recently, ROR2 has been demonstrated to promote OS cell migration and invasion. However, the role of ROR2 in the regulation of OS cell proliferation, as well as the underlying molecular mechanism, remains unclear. The present study aimed to investigate the underlying mechanism of ROR2 in osteosarcoma growth. Reverse transcription-quantitative polymerase chain reaction analysis and western blot analysis were used to examine the mRNA and protein expression. MTT assay, colony formation assay and cell cycle analysis were conducted to explore the function of ROR2 in osteosarcoma cells. In the present study, the expression of ROR2 was found to be frequently upregulated in OS tissues compared with matched adjacent normal tissues. It was also upregulated in the OS cell lines Saos-2, MG-63 and U-2 OS, relative to normal osteoblast hFOB 1.19 cells. Knockdown of ROR2 expression by transfection with ROR2-specific siRNA markedly inhibited the proliferation and colony formation of OS cells. Data from the cell cycle distribution assay revealed an accumulation of ROR2-knockdown cells in the G0/G1 phase, indicating that knockdown of ROR2 leads to an arrest in cell cycle progression. Mechanistic investigation revealed that the protein levels of c-myc, a target gene of the Wnt signaling, as well as cyclin D1, cyclin E and cyclin-dependent kinase 4 were markedly reduced in the ROR2-knockdown OS cells, suggesting that the inhibitory effect of ROR2 knockdown on OS cell proliferation is associated with the Wnt signaling pathway. In summary, the current study indicates an important role for ROR2 in the proliferation of OS cells. Therefore, ROR2 may be a promising therapeutic target in OS.

Objective Decoy receptor 3 (DcR3), a member of the tumor necrosis factor receptor superfamily, is amplified and over-expressed in various cancers. The objective of the present study was to investigate the concentration of DcR3 in sera of hepatocellular carcinoma (HCC) patients and its clinical significance. Methods Serum concentrations of DcR3 were measured by enzyme-linked immunosorbent assay (ELISA) in 67 patients with HCC, 8 with liver cirrhosis, 17 with cholecystitis, and in 28 healthy individuals. Immunohistochemistry was employed to access protein expression of DcR3 in the corresponding HCC tissues. Results Serum concentrations of DcR3 in patients with HCC or cirrhosis were significantly higher than in healthy individuals (P < 0.01). Moreover, serum concentrations of DcR3 in HCC patients were associated with TNM stage, para-cirrhosis, capsular infiltration, and metastasis or recurrence of disease (P < 0.05). There was a positive correlation between the serum concentration of DcR3 and protein expression in HCC tissues (r = 0.472, P < 0.01). Conclusions The high serum concentration of DcR3 might play a certain role in pathogenesis, progress, and metastasis of HCC. Moreover, DcR3 might serve as a valuable molecular indicator in early diagnosis and contribute to predicting the clinical outcome in HCC patients.

Chemotherapy has been reported to induce epithelial-mesenchymal transition (EMT) in tumor cells, which is a critical step in the process of metastasis leading to cancer spreading and treatment failure. However, the underlying mechanisms of chemotherapy-induced EMT remain unclear, and the involvement of microRNAs (miRNA) in this process is poorly understood. To address these questions, we established stable chemotherapy-resistant tongue squamous cell carcinoma (TSCC) cell lines CAL27-res and SCC25-res by exposing the parental CAL27 and SCC25 lines to escalating concentrations of cisplatin for 6 months. CAL27-res and SCC25-res cells displayed mesenchymal features with enhanced invasiveness and motility. MiRNA microarray illustrated that miR-200b and miR-15b were the most significantly downregulated microRNAs in CAL27-res cells. Ectopic expression of miR-200b and miR-15b with miRNA mimics effectively reversed the phenotype of EMT in CAL27-res and SCC25-res cells, and sensitized them to chemotherapy, but inhibition of miR-200b and miR-15b in the sensitive lines with anti-sense oligonucleotides induced EMT and conferred chemoresistance. Retrieving the expression of B lymphoma Mo-MLV insertion region 1 homolog (BMI1), a target for miR-200b and miR-15b, in the presence of the miRNA mimics by transfecting CAL27-res cells with pcDNA3.1-BMI1-carrying mutated seed sequences of miR-200b or miR-15b at its 3'-UTR recapitulated chemotherapy-induced EMT. In vivo, enforced miR-200b or miR-15b expression suppressed metastasis of TSCC xenografts established by CAL27-res cells. Clinically, reduced miR-200b or miR-15b expression was associated with chemotherapeutic resistance in TSCCs and poor patient survival. Our data suggest that reduced expression of miR-200b and miR-15b underscores the mechanisms of chemotherapy-induced EMT in TSCC, and may serve as therapeutic targets to reverse chemotherapy resistance in tongue cancers.