ETS variant 5 promotes colorectal cancer angiogenesis by targeting platelet-derived growth factor BB.

ETS transcription factors play important roles in tumor cell invasion, differentiation and angiogenesis. In this study, we initially demonstrated that ETS translocation variant 5 (ETV5) is abnormally upregulated in colorectal cancer (CRC), is positively correlated with CRC tumor size, lymphatic metastasis and tumor node metastasis (TNM) stage and indicates shorter survival and disease-free survival in CRC patients. In vitro and in vivo experiments revealed that the downregulation of ETV5 could significantly suppress CRC cell proliferation. Moreover, overexpression of ETV5 could stimulate CRC angiogenesis in vitro and in vivo, which is consistent with RNA-seq results. Then, we identified platelet-derived growth factor BB (PDGF-BB) as a direct target of ETV5 that plays an important role in ETV5-mediated CRC angiogenesis through an angiogenesis antibody microarray. Additionally, PDGF-BB could activate VEGFA expression via the PDGFR-ß/Src/STAT3 pathway in CRC cells and appeared to be positively correlated with ETV5 in CRC tissues. Finally, we revealed that ETV5 could bind directly to the promoter region of PDGF-BB and regulate its expression through ChIP and luciferase assays. Overall, our study suggested that the transcription factor ETV5 could stimulate CRC malignancy and promote CRC angiogenesis by directly targeting PDGF-BB. These findings suggest that EVT5 may be a potential new diagnostic and prognostic marker in CRC and that targeting ETV5 might be a potential therapeutic option for inhibiting CRC angiogenesis.

LIFR promotes tumor angiogenesis by up-regulating IL-8 levels in colorectal cancer.

Leukemia inhibitory factor receptor (LIFR) has been documented as a cancer promoter and to be present at high levels in various types of tumor tissues. In our search for molecules prognostic of colorectal cancer (CRC), we found high levels of LIFR in CRC tissue samples. Further analyses revealed that LIFR was indeed prognostic of CRC patient survival, and was associated with tumor size, lymphatic metastasis and stages. LIFR was found to promote tumor growth, metastasis and angiogenesis both in vitro and in vivo. High levels of LIFR in CRC facilitated proliferation and migration of endothelial cells, resulting in an increase in angiogenic activity. Moreover, interleukin 8 (IL-8) was found to play a role in the LIFR induced angiogenesis. IL-8 levels were correlated with LIFR levels in CRC tissues, whereas depletion of IL-8 led to a reduced angiogenic activity of LIFR in CRC cells. In addition, LIFR increased phosphorylation level of Erk, which regulates il-8 transcription. We conclude that LIFR is possibly a valuable prognostic marker for CRC. Our results also implicate a mechanism by which LIFR regulates tumor angiogenesis through Erk/IL-8 pathway, and that LIFR could be a potential therapeutic target for CRC.

MicroRNA-378-5p suppresses cell proliferation and induces apoptosis in colorectal cancer cells by targeting BRAF.

MicroRNAs (miRNAs) are a group of small non-coding RNA molecules that potentially play a critical role in tumorigenesis. Increasing evidences indicate that miR-378-5p is dysregulated in numerous human cancers including colorectal cancer (CRC) which hypothesizes that miR-378-5p may play an important role in tumorigenesis. However, its role in CRC carcinogenesis remains poorly defined because of lacking target genes information. In the present study, it was demonstrated that the expression of miR-378-5p was down-regulated in CRC tissues and cell lines as determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Furthermore, overexpression of miR-378-5p suppressed cell proliferation, as indicated by CCK-8 assay. Flow cytometric analysis demonstrated that overexpression of miR-378-5p induced cell cycle arrest and promoted apoptosis in CRC cells. A luciferase reporter assay indicated that BRAF was a direct target of miR-378-5p. Western blot and qRT-PCR analysis indicated that BRAF was significantly down-regulated by miR-378-5p in CRC cells. Moreover, miR-378-5p was negatively associated with BRAF in CRC tissues compared to adjacent non-tumor tissues. These results demonstrate that down-regulation of miR-378-5p promotes CRC cells growth by targeting BRAF and restoration of their levels is a potentially promising therapeutic in CRC.

Outcomes of Surgical Treatment for Graves' Disease: A Single-Center Experience of 216 Cases.

BACKGROUND: The role of surgery in the treatment of Graves' disease (GD) needs to be revisited. The aims of the present retrospective study were to evaluate the outcomes of the current surgical strategy as a definitive treatment of GD at our center and to explore the clinical association between GD and thyroid cancer. METHODS: A patient cohort of 216 cases from 2013 to 2020 was involved in this retrospective study. The data of the clinical characteristics and follow-up results were collected and analyzed. RESULTS: There were 182 female and 34 male patients. The mean age was 43.9 ± 15.0 years old. The mean duration of GD reached 72.2 ± 92.7 months. Of the 216 cases, 211 had been treated with antithyroid drugs (ATDs) and hyperthyroidism had been completely controlled in 198 cases. A total (75%) or near-total (23.6%) thyroidectomy was performed. Intraoperative neural monitoring (IONM) was applied to 37 patients. The failure of ATD therapy (52.3%) was the most common surgical indication, followed by suspicion of a malignant nodule (45.8%). A total of 24 (11.1%) patients had hoarseness after the operation and 15 (6.9%) patients had transient vocal cord paralysis; 3 (1.4%) had this problem permanently. No bilateral RLN paralysis occurred. A total of 45 patients had hypoparathyroidism and 42 of them recovered within 6 months. Sex showed a correlation with hypoparathyroidism through a univariate analysis. A total of 2 (0.9%) patients underwent a reoperation because of hematomas. A total of 104 (48.1%) cases were diagnosed as thyroid cancer. In most cases (72.1%), the malignant nodules were microcarcinomas. A total of 38 patients had a central compartment node metastasis. A lateral lymph node metastasis occurred in 10 patients. Thyroid carcinomas were incidentally discovered in the specimens of 7 cases. The patients with concomitant thyroid cancer had a significant difference in body mass index, duration of GD, gland size, thyrotropin receptor antibodies and nodule(s) detected. CONCLUSION: Surgical treatments for GD were effective, with a relatively low incidence of complications at this high-volume center. Concomitant thyroid cancer is one of the most important surgical indications for GD patients. Careful ultrasonic screening is necessary to exclude the presence of malignancies and to determine the therapeutic plan.

GANT61 suppresses cell survival, invasion and epithelial-mesenchymal transition through inactivating AKT/mTOR and JAK/STAT3 pathways in anaplastic thyroid carcinoma.

Glioma-associated oncogene (Gli) antagonist-61 (GANT61) not only suppresses the malignant behavior of several cancers but also presents synergistic effects with other anticancer agents on suppressing the progression of cancers, while relevant information is rare in anaplastic thyroid carcinoma (ATC). This study aimed to explore the therapeutic effect of GANT61 in ATC and its molecular mechanism. ATC cells (8505C and CAL-62) were treated with GANT61, followed by detection of cell proliferation, apoptosis, invasion and epithelial-mesenchymal transition (EMT) markers. Subsequently, RNA sequencing was performed to explore the potential downstream pathway. Following that, rescue experiments were conducted by SC79 (AKT activator) or colivelin (STAT3 activator) monotreatment or combined with GANT61 in ATC cells. GANT61 reduced Gli1 expression, suppressed proliferation at several time settings, promoted apoptosis, inhibited invasion and increased E-cadherin while decreased Vimentin and Snail expressions (EMT markers) in ATC cells. The subsequent RNA sequence identified 85 upregulated differentially expressed genes (DEGs) and 71 downregulated DEGs in GANT61-treated ATC cells, which were mainly enriched in PI3K/AKT, JAK/STAT, Hedgehog and mTOR pathways. Next, the inactivation of AKT/mTOR and JAK/STAT3 pathways by GANT61 treatment was verified by western blot. The following rescue experiments showed that SC79 or colivelin treatment promoted the malignant behaviors of ATC cells. More importantly, SC79 or colivelin treatment compensated the effect of GANT61 treatment on cell proliferation at several time settings and apoptosis, invasion, and part of that on EMT in ATC cells. GANT61 suppresses cell survival, invasion and EMT through inactivating AKT/mTOR or JAK/STAT3 pathways in ATC.

Predictive factors for prolonged operative time of robotic thyroidectomy via bilateral axillo-breast approach: Analysis of 359 cases of differentiated thyroid cancer.

OBJECTIVE: This study assessed the results of robotic thyroidectomy for differentiated thyroid cancer in early stage, to identify the predictive factors of operative time and complication rate. METHODS: A patient cohort of 359 cases in total was involved in this retrospective study. The data of clinical characteristics and follow-up results were collected. RESULTS: The cohort of patients involved was composed of 285 female patients and 74 male ones. The mean age was 34.91 ± 7.93 years old. The mean Body Mass Index (BMI) was 22.43 ± 3.47. The mean tumor size was 0.75 ± 0.56 cm, and the mean gland size was 4.68 ± 0.83 cm. Among all the specimen, the ratio of tumor invasion of gland capsule was 63/296, and the ratio of chronic thyroiditis was 110/249. 75 patients underwent total thyroidectomy + central compartment node dissection (CCND). 284 patients underwent Lobectomy + CCND. The ratio of central lymph node metastasis was 144/215 (40.1%). The mean number of lymph node dissected was 5.26 ± 4.09. The mean operative time was 96.53 ± 25.69 min. 21(5.8%) patients had hoarseness after operation. 22(29.3%) patients had hypocalcemia after total thyroidectomy. The inadvertent parathyroidectomy was found in 66(18.4%) cases. The surgical extent (unilateral/bilateral resection), BMI and gland size were found to have a significantly correlation with the operative time (p < 0.05) after multivariate analysis. CONCLUSION: The surgical extent, BMI and gland size are found to be independent risk factors of prolonged operative time of robotic thyroidectomy. However, these factors are not associated with a higher complication rate.

Robotic thyroidectomy via bilateral axillo-breast approach: Experience and learning curve through initial 220 cases.

OBJECTIVE: This study is aim to summarize the experience of robotic thyroidectomy via bilateral axillo-breast approach of our center and also to find out the learning curve of this technique. METHODS: In total 220 initial patients who have undergone robotic thyroidectomy via bilateral axillo-breast approach from May 2015 to September 2017 were involved in this study. The data of operation time, clinical characteristics, surgical outcomes and oncological outcomes were collected. The moving average method is use to explore the learning curve. RESULTS: All patients had undergone robotic thyroidectomy successfully without conversion to other surgical approaches. The mean age of the enrolled subjects was 34.4 ± 7.8 years old, while the sex ratio (male/female) was 38/182. There were 50 benign tumor cases and 170 malignant tumor cases. The mean total operation time was 105.3 ± 37.6 min. Lymph node metastasis was observed in 61 (35.9%) patients. The mean retrieved lymph node count was 5.1 ± 3.8 while the mean metastatic lymph node count was 0.7 ± 1.5. The operation time decreased significantly after about 30-35 cases and formed the plateau. After 80 cases, the operation time significantly decreased again. CONCLUSION: For skilled endocrine surgeons, robotic thyroidectomy has proved to be safe and feasible, which could be applied extensively in patients strictly selected in high-volume centers, with a relatively short learning curve of about 30-35 cases. While the surgeons getting more experienced, this technique would be more efficient.

Targeting autophagy enhances apatinib-induced apoptosis via endoplasmic reticulum stress for human colorectal cancer.

Apatinib, a novel tyrosine kinase inhibitor (TKI), has been confirmed for its efficacy and safety in the treatment of advanced gastric carcinoma and some other solid tumors. However, the direct functional mechanisms of tumor lethality mediated by apatinib have not yet been fully characterized, and the precise mechanisms of drug resistance are largely unknown. Here, in this study, we demonstrated that apatinib could induce both apoptosis and autophagy in human colorectal cancer (CRC) via a mechanism that involved endoplasmic reticulum (ER) stress. Moreover, activation of the IRE1α pathway from apatinib-induced ER stress is responsible for the induction of autophagy; however, blocking autophagy could enhance the apoptosis in apatinib-treated human CRC cell lines. Furthermore, the combination of apatinib with autophagy inhibitor chloroquine (CQ) tends to have the most significant anti-tumor effect of CRC both in vitro and in vivo. Overall, our data show that because apatinib treatment could induce ER stress-related apoptosis and protective autophagy in human CRC cell lines, targeting autophagy is a promising therapeutic strategy to relieve apatinib drug resistance in CRC.

[Predictive factors for locally recurrent rectal cancer after primary curative surgery].

Local recurrence is a major clinical challenge after primary rectal cancer surgery. Although there is a possibility that R0 resection can be achieved, the outcome is still not favorable due to the low R0 resection rate and complexity of the surgery. Therefore prevention has a higher priority over treatment afterwards. As TME principle is accepted worldwide, the local recurrence rate has been reduced dramatically. And there are other factors associated with local recurrence including CRM, operation type, staging and PNI. Proper chemoradiotherapy may reduce the risk, however benefit always comes with side effect, therefore risk stratification is important.