A predictive model for patients with local-regionally advanced oropharyngeal squamous cell carcinoma treated after cervical lymph node dissection.

PURPOSE: To develop a nomogram to predict the cancer-specific survival of patients with local-regionally advanced oropharyngeal squamous cell carcinoma after cervical lymph node dissection. METHODS: The clinical variables of patients confirmed as having oropharyngeal squamous cell carcinoma between 2008 and 2015 were retrieved from the Surveillance, Epidemiology and End Results database. Univariate and multivariate analysis were performed, followed by the construction of nomograms for CSS. Nomogram' accuracy was evaluated through the concordance index, calibration curves and decision curve analysis. RESULTS: A total of 1994 oropharyngeal squamous cell carcinoma patients who underwent surgery were included in this study. Sex, T-stage, American Joint Committee on Cancer-stage, positive lymph nodes, positive lymph node ratio, log odds of positive lymph nodes, and postoperative radiotherapy were selected to establish the nomogram for oropharyngeal squamous cell carcinoma. The concordance index of the nomogram was 0.747 (95% CI 0.714-0.780) in the training calibration cohort and 0.735 (95% CI 0.68-0.789) in the validationcohort and the time-dependent Area under the curve (> 0.7) indicated satisfactory discriminative ability of the nomogram. The calibration plot shows that there is a good consistency between the predictions of the nomogram and the actual observations in the training and validation cohorts. In addition, decision curve analysis showed that the nomogram was clinically useful and had a better ability to recognize patients at high risk than the American Joint Committee on Cancer tumor-node-metastasis staging. CONCLUSION: The predictive model has the potential to provide valuable guidance to clinicians in the treatment of patients with locoregionally advanced OPSCC confined to the cervical lymph nodes.

CircRTN1 acts as a miR-431-5p sponge to promote thyroid cancer progression by upregulating TGFA.

PURPOSE: This study aimed to explore the role and underlying mechanism of circular RNA (circRNA) reticulon 1 (circRTN1) in thyroid cancer (TC). METHODS: The expression levels of circRTN1, microRNA-431-5p (miR-431-5p), and transforming growth factor-alpha (TGFA) mRNA were measured by quantitative real-time PCR (qRT-PCR). Cell proliferation was evaluated using colony formation and 5-ethynyl-2'-deoxyuridine (EdU) assays. Cell apoptosis was analyzed using flow cytometry. Cell migration and invasion were measured using the transwell assay. The protein levels of ki-67, Bax, matrix metalloproteinase 2 (MMP-2), and TGFA were detected using Western blot assay. The interaction between miR-431-5p and circRTN1 or TGFA was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. The effect of circRTN1on TC in vivo was explored via xenograft tumor assay. RESULTS: The expression of circRTN1 was increased in TC tissues and cells. Knockdown of circRTN1 suppressed TC cell proliferation, migration, and invasion, and increased cell apoptosis. MiR-431-5p was a target of circRTN1, and miR-431-5p downregulation reversed the role of circRTN1 knockdown in TC cells. TGFA was identified as a direct target of miR-431-5p, and miR-431-5p exerted the anti-tumor role in TC cells by downregulating TGFA. Moreover, circRTN1 sponged miR-431-5p to regulate TGFA expression. Furthermore, circRTN1 knockdown inhibited tumor growth in vivo. CONCLUSION: CircRTN1 acted as a cancer-promoting circRNA in TC by regulating the miR-431-5p/TGFA axis, providing a potential therapeutic strategy for TC treatment.

The effects of radiotherapy after thoracic and laparoscopic surgery on patients with esophageal cancer and on their prognoses.

OBJECTIVE: This paper aimed to explore the effects of radiotherapy after thoracic and laparoscopic surgery (TLS) in patients with esophageal cancer and on their prognoses. METHODS: Altogether 118 patients with esophageal cancer diagnosed in our hospital were recruited as the study cohort and randomly divided into a postoperative radiotherapy group (59 cases) and a postoperative chemotherapy group (59 cases). All the patients were treated with TLS. In addition to the TLS, the patients in the postoperative radiotherapy group underwent radiotherapy, and the patients in the postoperative chemotherapy group were administered cisplatin and 5-fluorouracil (PF) chemotherapy. Before the treatment and at 6 months after the treatment, the serum carbohydrate antigen 199 (CA199), carbohydrate antigen 153 (CA153), and carcinoembryonic antigen (CEA) levels were measured using immunity transmission turbidity (ITT). The expression levels of Bax and Bcl-2 in the peripheral blood mononuclear cells (PBMCs) were measured using Western blot (WB). The CD4+, CD8+ and CD3+ levels in the peripheral venous blood were measured using a flow cytometer. The two groups were compared in terms of their effective treatment rates, their incidences of complications, and their postoperative survival rates. RESULTS: After the treatment, the serum CEA, CA153, and CA199 levels in the postoperative radiotherapy group were significantly lower than they were in the postoperative chemotherapy group (P<0.05). After the treatment, the expression level of Bcl-2 was significantly lower in the postoperative radiotherapy group, but the Bax expression level was significantly higher in the postoperative radiotherapy group (P<0.05). After the treatment, there were no statistically significant differences in the CD4+, CD3+ or CD8+ levels between the two groups (P>0.05). After the treatment, the overall response rate (ORR) and the total incidence of adverse reactions were significantly higher in the postoperative radiotherapy group (P<0.05). After the treatment, the 1-year, 3-year, and 5-year survival rates were significantly elevated in the postoperative radiotherapy group (P<0.05). CONCLUSION: Compared with the esophageal cancer patients treated with chemotherapy after TLS, the serum CA153, CA199, and CEA levels were significantly improved in the patients treated with radiotherapy. The Bcl-2 and Bax levels in the PBMCs tended close to normal. Therefore, undergoing radiotherapy after TLS is markedly effective in prolonging patients' survival times and improving their prognoses.

Correlation between miR-138-5p expression and efficacy of platinum-based chemotherapy in advanced gastric cancer patients.

BACKGROUND: We investigated the relationship between levels of microRNA (miR)-138-5p in plasma and tumor tissues from advanced gastric cancer patients, and the efficacy of first-line platinum-based chemotherapy. METHODS: MiR-138-5p expression was measured by qRT-PCR in cancerous tissues and plasma from 51 advanced gastric cancer patients, in paracancerous tissues and in plasma from healthy volunteers as control. All patients received first-line platinum-based chemotherapy. Correlations between miR-138-5p expression and the treatment efficacy, progression-free survival (PFS), and overall survival (OS) of first-line chemotherapy were evaluated. RESULTS: Significantly lower levels of miR-138-5p were detected in gastric cancer tissues compared with paracancerous tissues and in the plasma of patients compared with control subjects (both P<0.05). A positive correlation was detected between the treatment efficacy and miR-138-5p expression in both cancer tissues and plasma (P<0.05). Receiver-operating characteristic (ROC) curves were constructed to determine the optimal miR-138-5p cutoff value for predicting the efficacy of platinum-based chemotherapy. Patients with high miR-138-5p expression in either tissues (≥0.081) or plasma (≥0.047) had better treatment responses and longer PFS and OS than patients with low miR-138-5p expression (P<0.05), and multivariate analyses confirmed miR-138-5p expression as a promising prognostic biomarkers. CONCLUSIONS: Our study suggested that miR-138-5p expression in cancer tissues or plasma could be a useful predictive biomarker for the efficacy of platinum-based chemotherapy and prognoses in advanced gastric cancer patients.

MicroRNA-362-5p enhances the cisplatin sensitivity of gastric cancer cells by targeting suppressor of zeste 12 protein.

Chemotherapy resistance is a major obstacle to the effective treatment of patients with gastric cancer (GC). Mounting evidence has indicated that the dysregulation of microRNAs (miRNAs) is associated with the sensitivity of cancer cells to chemotherapy. However, the mechanisms underlying miRNA-mediated chemoresistance in GC cells remain to be elucidated. The present study aimed to identify functional miRNAs that may regulate the sensitivity of human GC cells to cisplatin (DDP) treatment. miRNA microarray analysis was used to identify differentially expressed miRNAs between the human cisplatin-sensitive GC cell line SGC7901 and the corresponding cisplatin-resistant cell line SGC7901/DDP. miRNA (miR)-362-5p, which is associated with numerous types of tumors, was identified to be downregulated in the SGC7901/DDP cell line. However, the biological role of miR-362-5p in SGC7901/DDP cells remains to be explored. The expression level of miR-362-5p was demonstrated to be reduced in SGC7901/DDP cells compared with SGC7901 cells by reverse transcription-quantitative PCR. Upregulation of miR-362-5p significantly increased cisplatin sensitivity and cisplatin-induced apoptosis, whereas downregulation of miR-362-5p attenuated these effects. Databases predicted that suppressor of zeste 12 protein (SUZ12) may function as a target of miR-362-5p. In addition, the mRNA and protein expression levels of SUZ12 in SGC7901/DDP cells were significantly higher compared with SGC7901 cells and negatively associated with miR-362-5p expression. MTT and western blot analysis assays confirmed that knockdown of SUZ12 enhanced cisplatin sensitivity and decreased NF-κB/p65 protein levels in SGC7901/DDP cells. In addition, upregulation of miR-362-5p in SGC7901/DDP cells decreased the protein expression level of SUZ12, whereas downregulation of miR-362-5p increased the SUZ12 expression level. The results of the present study suggested that dysregulated miR-362-5p may target SUZ12 to promote the development of cisplatin resistance and attenuate cisplatin-induced apoptosis. Therefore, miR-362-5p upregulation combined with cisplatin treatment may serve as a promising therapeutic strategy for patients with cisplatin-resistant GC.

MicroRNA-200c reverses drug resistance of human gastric cancer cells by targeting regulation of the NER-ERCC3/4 pathway.

Gastric cancer (GC) is one of the most common types of malignant tumor. Due to the lack of effective drugs and the emergence of chemotherapy resistance, patients with GC exhibit a poor prognosis and low survival rate. MicroRNAs (miRNAs/miRs) serve an important role in drug resistance of different types of cancer. They may be suitable for use as biomarkers in the diagnosis, treatment and prognosis of tumors. The present study aimed to investigate the molecular mechanism underlying the ability of miR-200c-3p to reverse drug resistance in a SGC7901/DDP GC cell line, particularly its effects on the ERCC excision repair 3, TFIIH core complex helicase subunit (ERCC3) and ERCC excision repair 4, endonuclease catalytic subunit (ERCC4) proteins in the nucleotide excision repair (NER) pathway. Reverse transcription-quantitative polymerase chain reaction demonstrated that miR-200c-3p expression in cisplatin-resistant SGC7901/DDP cells was lower than in parental SGC7901 cells, whereas the protein expression levels of ERCC3 and ERCC4 in these cells were higher by western blot analysis. In SGC7901/DDP-derived miR-200c-3p overexpressing cells, ERCC3 expression, ERCC4 expression and cisplatin resistance were decreased compared with in parental SGC7901/DDP cells and SGC7901/DDP-derived vector control cells. In SGC7901-derived miR-200c-3p knockdown cells, ERCC3 expression, ERCC4 expression and cisplatin resistance were increased compared with in parental SGC7901 cells and SGC7901-derived vector control cells. In conclusion, overexpression of miR-200c-3p may reverse drug resistance in the SGC7901/DDP GC cell line via downregulation of ERCC3 and ERCC4, which suggested this may be part of a mechanism involving the NER pathway.

MiR-192-5p reverses cisplatin resistance by targeting ERCC3 and ERCC4 in SGC7901/DDP cells.

Cisplatin chemoresistance is a clinical obstacle in the treatment of gastric cancer (GC). Enhanced DNA repair capacity may lead to cisplatin resistance. However, the detailed molecular mechanism of GC cisplatin resistance specifically involving nucleotide excision repair (NER) is not clear. However, the mechanism through which the NER pathway contributes to cisplatin resistance in GC is still unclear. In light of the crucial role of microRNAs (miRNAs) in regulating protein expression and biological behavior, we aimed to analyze the expression and function of miR-192-5p in the NER pathway and its role in cisplatin resistance in GC. Comet assays were performed to measure the amount of DNA damage and repair in the SGC7901 and SGC7901/DDP GC cell lines by observing the tail length. MiRNA expression levels in SGC7901/DDP and SGC7901 cells were detected by microarray. Quantitative real-time PCR (qRT-PCR) was carried out to confirm the expression level of miR-192-5p. Lentiviral vector transfection modifies miR-192-5p levels in SGC7901/DDP and SGC7901 cells. The IC50 values of cisplatin-treated cells were assessed by MTT assays. The protein level was determined by Western blot and immunohistochemistry. With enhanced DNA repair, the expression levels of ERCC3 and ERCC4 in SGC 7901DDP cells increased, while miR-192-5p was significantly downregulated in SGC7901/DDP compared with SGC7901 cells. ERCC3 and ERCC4 were identified as the main targets of miR-192-5p. Forced expression of miR-192-5p in SGC7901/DDP cells significantly inhibited the expression of ERCC3 and ERCC4, making GC cells more sensitive to cisplatin in vitro and in vivo. In contrast, knockdown of miR-192-5p expression in SGC7901 cells increased the expression of ERCC3 and ERCC4, resulting in cisplatin resistance in vitro and in vivo. MiR-192-5p partially reversed GC cisplatin resistance by targeting ERCC3 and ERCC4, which participate in the NER pathway, suggesting that miR-192-5p may be a potential biomarker and therapeutic target for GC cisplatin resistance.

miR­138­5p modulates the expression of excision repair cross­complementing proteins ERCC1 and ERCC4, and regulates the sensitivity of gastric cancer cells to cisplatin.

The microRNA (miR)­138­5p affects the chemotherapeutic sensitivity of several human cancer types. In the present study, the expression and regulatory mechanisms of miR­138­5p were investigated in the gastric cancer cell line SGC7901 and its cisplatin­resistant derivative SGC7901/DDP. Gene microarray and reverse transcription­quantitative polymerase chain reaction analyses revealed that miR­138­5p was expressed at significantly lower levels in SGC7901/DDP compared with SGC7901 cells. Using computational predictive algorithms, two proteins involved in the nuclear excision repair pathway were identified, excision repair cross­complementing (ERCC)1 and ERCC4, as putative miR­138­5p target genes. Western blot analysis confirmed that ERCC1 and ERCC4 expression levels were inversely proportional to miR­138­5p levels in SGC7901 and SGC7901/DDP cells. Furthermore, ERCC1 and ERCC4 were upregulated in SGC7901 cells expressing miR­138­5p­targeting short hairpin RNA and, conversely, downregulated in SGC7901/DDP cells overexpressing miR­138­5p, confirming that this miRNA regulates ERCC protein levels. Notably, miR­138­5p silencing enhanced the cisplatin resistance of SGC7901 cells, while miR­138­5p overexpression partially reversed the cisplatin resistance of SGC7901/DDP cells. Taken together, these data suggest that miR­138­5p regulates the sensitivity of gastric cancer cells to cisplatin, possibly by modulating expression of the DNA repair proteins ERCC1 and ERCC4.

MicroRNA-200c as a prognostic and sensitivity marker for platinum chemotherapy in advanced gastric cancer.

We examined microRNA-200c (miR-200c) expression in tumor tissues and plasma of patients with advanced gastric cancer and correlated miR-200c expression with treatment efficacy of platinum chemotherapy and patient prognosis. Tumor tissues were collected from 51 patients with advanced gastric cancer who received platinum-containing chemotherapies. The plasma was collected from the same group of patients and 51 subjects with chronic superficial gastritis. Quantitative RT-PCR was used to evaluate miR-200c expression, and its correlation with treatment efficacy and patient prognosis was analyzed. The results showed that the miR-200c expression in gastric cancer tissues and in plasma were significantly lower than tumor-adjacent tissues and in patients with chronic superficial gastritis (both p <0.05). No significant correlation was found between miR-200c expression in tumors or plasma and clinical characteristics. Patients with higher miR-200c expression had better treatment outcomes with platinum chemotherapy and longer progression-free survival and overall survival than patients with lower miR-200c expression. Receiver-operating characteristic curve analysis showed that miR-200c expression in gastric cancer tissues and plasma distinguished patients' treatment outcomes. Multivariate analyses confirmed that over expression of miR-200c both in gastric cancer tissue and plasma is associated with longer progression-free survival and overall survival. Taken together, our study indicated that miR-200c expression in gastric cancer tissues and plasma of patients with advanced gastric cancer is associated with better treatment efficacy and prognosis with platinum chemotherapy, suggesting that expression of miR-200c may be predictive for chemotherapy and prognosis in advanced gastric cancer patients.

Dysregulation of mRNA profile in cisplatin-resistant gastric cancer cell line SGC7901.

AIM: To explore novel therapeutic target of cisplatin resistance in human gastric cancer. METHODS: The sensitivity of SGC7901 cells and cisplatin-resistant SGC7901 cells (SGC7901/DDP) for cisplatin were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. High-quality total RNA which isolated from SGC7901/DDP cells and SGC7901 cells were used for mRNA microarray analysis. Results were analyzed bioinformatically to predict their roles in the development of cisplatin resistance and the expression of 13 dysregulated mRNAs we selected were validated by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: SGC7901/DDP cells highly resistant to cisplatin demonstrated by MTT assay. A total of 1308 mRNAs (578 upregulated and 730 downregulated) were differentially expressed (fold change ≥ 2 and P-value < 0.05) in the SGC7901/DDP cells compared with SGC7901 cells. The expression of mRNAs detected by qRT-PCR were consistent with the microarray results. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway and protein-protein interaction analysis demonstrated that the differentially expressed mRNAs were enriched in PI3K-Akt, Notch, MAPK, ErbB, Jak-STAT, NF-kappaB signaling pathways which may be involved in cisplatin resistance. Several genes such as PDE3B, VEGFC, IGFBP3, TLR4, HIPK2 and EGF may associated with drug resistance of gastric cancer cells to cisplatin. CONCLUSION: Exploration of those altered mRNAs may provide more promising strategy in diagnosis and therapy for gastric cancer with cisplatin resistance.