Cancer-associated fibroblast exosome LINC00355 promotes epithelial-mesenchymal transition and chemoresistance in colorectal cancer through the miR-34b-5p/CRKL axis.

This study was designed to investigate the role and mechanism of cancer-associated fibroblasts (CAFs)-derived exosomes (CAFs-exo) in metastatic and chemoresistant colorectal cancer (CRC). First, CAFs and normal fibroblasts (NFs) were isolated from CRC tissues and histologically normal adjacent tissues. Then, CAFs-exo and NFs-exo were separated with the help of ultracentrifugation. Next, the morphology, diameter and marker expression of exos were evaluated by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and western blot, respectively. Besides, real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression levels of LINC00355, miR-34b-5p, and CRKL in clinical tissue samples, CRC cells, fibroblasts and exos; MTT assay and cell colony formation assay to assess the chemoresistance and colony formation ability of CRC cells, respectively. Subsequently, the targeting relationship among LINC00355, miR-34b-5p, and CRKL (a target gene of miR-34b-5p) was verified by Luciferase reporter assay; and the binding relationship between LINC00355 and miR-34b-5p was assessed by a pull-down assay. Finally, the expression of epithelial-mesenchymal transition (EMT)-related proteins, and CRKL in cells or exos were detected using western blot. After a series of treatments, CAFs and NFs, CAFs-exo and NFs-exo were successfully isolated and identified. It could be observed that CAFs-exo promoted EMT, colony formation and multidrug resistance in CRC cells by secreting LINC00355. Further studies demonstrated that CAFs-exo-secreted LINC00355 increased the expression of CRKL via inhibiting the expression of miR-34b-5p, thereby enhancing chemoresistance and promoting EMT progression in CRC cells. Collectively, CAFs-exo-derived LINC00355 promotes EMT and chemoresistance in CRC by regulating the miR-34b-5p/CRKL axis.

Expression of ZNF281 in colorectal cancer correlates with response to radiotherapy and survival.

BACKGROUND: The treatment of Colorectal cancer (CRC) is extremely complex and survival rates vary depending on the stage of the disease at the time of diagnosis. Neoadjuvant chemoradiotherapy (NACRT), is the conventional treatment for locally advanced rectal cancer (LARC); however, the resistance to chemoradiotherapy in LARC is difficult to predict. MATERIALS AND METHODS: In this study, clinical data of 126 LARC patients were collected and analyzed, and relevant validation was performed using GEO database and in vitro and in vivo experiments, including Western blotting and Real-time quantitative PCR, immunohistochemistry, immunofluorescence, clonogenic cell survival assays, and nude-mouse xenograft models. RESULTS: In patients with LARC who were treated with neoadjuvant radiotherapy (NART), higher ZNF281 expression in malignant tissue was associated with a poorer prognosis and lesser degree of tumor regression. Cell and mouse experiments have shown that ZNF281 reduces the damage caused by X-rays to CRC cells and tumors grown in mice. CONCLUSION: We found that the expression of ZNF281 predicted the radiation response of CRC cells and suggested the prognosis of patients with LARC who received neoadjuvant radiation therapy.

Circular RNA SMARCA5 inhibits gastric cancer progression through targeting the miR-346/ FBXL2 axis.

Circular RNA (circRNA) SMARCA5 (circSMARCA5) is a cancer-related circRNA that has been observed to be involved in the progression of several types of cancer. However, the role of circSMARCA5 in gastric cancer has not been reported. In the present study, we aimed to explore the function and mechanism of circSMARCA5 in gastric cancer. Our results showed that circSMARCA5 expression was significantly decreased in human gastric cancer tissues and cell lines. Further in vitro investigations demonstrated that overexpression of circSMARCA5 in SGC7901 cells inhibited cell proliferation, migration and invasion. Luciferase reporter assays proved that circSMARCA5 acted as a sponge for miroRNA-346 (miR-346) and regulated the expression of F-Box and leucine rich repeat protein 2 (FBXL2). Furthermore, transfection of miR-346 mimics into cells overexpressing circSMARCA5 blocked the function of circSMARCA5. Finally, we found that knockdown FBXL2 significantly reversed the effects of miR-346 inhibitor on gastric cell proliferation, migration and invasion. Collectively, circSMARCA5 exhibited a tumor suppressor-like activity in gastric cancer via regulating the miR-346/FBXL2 axis.

Silencing of FOXO6 inhibits the proliferation, invasion, and glycolysis in colorectal cancer cells.

Forkhead box class O6 (FOXO6) is an important member of FOXO family, which has been demonstrated to be implicated in tumor development. However, the role of FOXO6 in colorectal cancer (CRC) is still unclear. The study aimed to investigate the potential roles of FOXO6 in the development of CRC. Our results showed that FOXO6 was overexpressed in CRC tissues and cell lines. FOXO6 knockdown inhibited cell proliferation, as well as repressed the migration and invasion of CRC cells. Additionally, we found that FOXO6 knockdown altered cellular metabolism by inhibiting glycolysis and promoting mitochondrial respiration. Furthermore, FOXO6 knockdown inhibited the activation of PI3K/Akt/mTOR pathway in CRC cells. The results herein indicated that FOXO6 knockdown inhibited cell proliferation, migration, invasion, and glycolysis in CRC cells. PI3K/Akt/mTOR pathway was involved in the effects of FOXO6 on CRC cells. These findings suggested that FOXO6 might be a potential target for the CRC therapy.

Knockdown of A-kinase anchor protein 4 inhibits hypoxia-induced epithelial-to-mesenchymal transition via suppression of the Wnt/ß-catenin pathway in human gastric cancer cells.

Hypoxia induces epithelial-mesenchymal transition (EMT) in tumorigenesis. A-kinase anchor protein 4 (AKAP4) is a member of AKAPs family and plays a critical role in tumorigenesis. However, the biological role of AKAP4 in gastric cancer remains unknown. Thus, we investigated the effect of AKAP4 on EMT in human gastric cancer cells under hypoxic conditions. Our results showed that AKAP4 expression was significantly upregulated in human gastric cancer cell lines. In addition, silenced expression of hypoxia-inducible factor-1α markedly suppressed AKAP4 expression in gastric cancer cells under hypoxia. Furthermore, knockdown of AKAP4 significantly prevented hypoxia-induced migration, invasion, and EMT process in gastric cancer cells. Mechanistically, knockdown of AKAP4 prevented the activation of the Wnt/ß-catenin pathway in gastric cancer cells under hypoxia condition. These findings indicate that knockdown of AKAP4 inhibits hypoxia-induced EMT in human gastric cancer cells, at least in part, via inactivation of the Wnt/ß-catenin signaling pathway. It is, therefore, AKAP4 may be a potential therapeutic target for the treatment of gastric cancer.

A comparison of surgical procedures and postoperative cares for minimally invasive laparoscopic gastrectomy and open gastrectomy in gastric cancer.

Minimally invasive, laparoscopic gastrectomy (LG) has assumed an ever-expanding role in gastric cancer treatment. Accumulating data so far seem to suggest that LG is at least a viable alternative of conventional open gastrectomy (OG) in different contexts. However, even though reviews and meta-analyses have compared the advantages and limitations of each option, it is still controversial whether LG is a better alternative to OG, especially in advanced gastric cancer (AGC). The major goal of this study is to evaluate the readouts of LG, in comparison with OG. A literature search was performed for studies published from 2009 to 2013. Medical records of 20868 gastric cancer patients from 32 independent studies were reviewed and analyzed. All 32 studies concluded that LG is at least comparable with OG. LG is superior to OG in offering less blood loss, shorter hospital stay, and lower risk of complications, although LG is probably inferior in operative time, and not different from OG in mortality. Considering the merits and the potential future technical improvement, it is reasonable to speculate that LG may eventually replace OG in most clinical contexts.

Systemic analysis on laparoscope-assisted gastrectomy for patients with gastric cancer.

BACKGROUND: Laparoscope-assisted gastrectomy in treating patients with gastric cancers developed with a background of highly invasive traditional surgery and is being increasingly performed in the Asian Pacific area. This study systemically investigated the technique and clinical results for comparison with traditional radical subtotal gastrectomy for gastric cancers. METHODS: Clinical studies evaluating the effectiveness and side effects of laparoscope-assisted gastrectomy in treating patients with gastric cancers were identified using a predefined search strategy. Summary rates of effectiveness and side effects of laparoscope-assisted gastrectomy were calculated. RESULTS: Thirteen clinical studies which including 1,412 patients with gastric cancer treated by laparoscope-assisted gastrectomy were considered eligible for inclusion. Systemic analysis showed that, for all patients, the pooled resection rate was 100%. Major adverse effects were anastomotic stenosis, abdominal abscess, abdominal bleeding, postoperative ileus. Treatment related death occurred in 0. 71% (10/1412). CONCLUSION: This systemic analysis suggests that laparoscope-assisted gastrectomy in treating patients with gastric cancers is associated with good curative rate and acceptable complications.