Cisplatin remains to be primary chemotherapeutic drug for gastric cancer patients, especially for advanced stage ones. However, primary or acquired resistance often occurs with the mechanisms being not well understood, which results in relapse of the cancer and poor survival. Herein, we found that HER2 upregulation was associated with cisplatin resistance. We observed that cisplatin-resistant gastric cancer cells underwent a morphological change similar to epithelial-mesenchymal transition (EMT) which is mediated by HER2 overexpression. When specific monoclonal antibody Herceptin, small molecular targeted drug CP724714, or small interfering RNA against HER2 was applied, the EMT-like phenotypic change was dramatically reversed. More importantly, the IC50 and Resistance Index of resistant gastric cancer cells to cisplatin were also decreased by any of these treatments.We demonstrated that expression and amplification of HER2 positively correlated with expression of EMT-related transcription factor Snail in gastric cancer tissues. Furthermore, for the first time, we found that HER2/Snail double positive gastric cancer patients had poorer survival than single positive or double negative counterparts, which provided experimental evidence for the necessity of HER2/Snail double testing in gastric cancer. In conclusion, this study provides some clues of the association of cisplatin resistance with HER2 upregulation-induced EMT in gastric cancer cells.
Tumor invasion and metastasis are the most common causes of death in gastric carcinoma. Twist, a transcription factor of the basic helix-loop-helix class, reportedly regulates cancer metastasis and induces epithelial-mesenchymal transition (EMT). We evaluated the expression of Twist and its effect on cell migration in gastric carcinoma (GC). Twist expression was detected by real-time quantitative RT-PCR in gastric tumor tissue, metastatic lymph nodes and normal gastric tissue from 47 gastric carcinoma patients who had undergone gastrectomies with radical lymph node dissections without preoperative treatment. Twist expression was also analyzed immunohistochemically in 436 gastric cancer cases. GC tumor tissue and metastatic lymph nodes was upregulated compared with normal gastric mucosa (P < 0.05). Twist protein expression differed significantly among gastric tumor tissue, matched normal gastric mucosa, and lymph nodes (P < 0.05) In stages I, II, and III, 5-year survival rates of patients with high Twist expression were significantly lower than in patients with low expression (P < 0.05). In stage IV, Twist expression did not correlate with 5-year survival rates (P = 0.07). Further multivariate analysis suggested that depth of invasion, lymph-node and distant metastases, TNM stage, and up-regulation of TWIST were independent prognostic indicators for GC. Twist expression in gastric cancer is associated significantly with lymph-node and distant metastases, and poor prognosis. Twist may be a useful marker for the development, progression and metastasis of GC.
Increased expression of HOXB7 has been reported to correlate with the progression in many cancers. However, the specific mechanism by which it promotes the evolution of gastric cancer (GC) is poorly understood.In this study, we sought to investigate the role of HOXB7 in GC by assessing HOXB7 expression in patient tissue and its correlation to clinical characteristics. We found that GC tissues showed increased expression of HOXB7 and that the HOXB7 expression was significantly associated with Lauren classification, invasion depth, lymphatic metastasis and poor prognosis, and could serve as an independent prognostic factor. To further investigate the role of HOXB7 in GC, we generated stable GC cell lines and both over-expressed and knocked down HOXB7 expression. Over-expression of HOXB7 in GC cell lines enhanced cell proliferation, colony formation, migration and invasion ability, whereas the opposite trends were observed upon reduction of HOXB7 expression by knockdown. These findings were further supported by our in vivo studies which show that HOXB7 expression can affect the GC cells' subcutaneous growth and lung metastases. A Phospho-MAPK Array Kit was used to explore the possible mechanism of HOXB7-induced cell proliferation and invasion. We found that the AKT signaling pathway and the two members of the MAPK pathway, were involved in those promoting effects. In conclusion, our results showed that increased expression of HOXB7 might play an important role in promoting GC proliferation, migration and invasion by inducing both AKT and MAPK pathways, thus resulting in progression of, and poor prognosis in GC patients.
Background Inspired by nature, the biomimetic approach has been incorporated into drug nanocarriers for cancer targeted chemotherapy. The nanocarriers are cloaked in cell membranes, which enables them to incorporate the functions of natural cells. Key scientific concepts of review Nanocarriers surface engineered with cell membranes have emerged as a fascinating source of materials for cancer targeted chemotherapy. A distinctive characteristic of cell membrane-coated nanocarriers (CMCNs) is that they include carbohydrates, proteins, and lipids, in addition to being biocompatible. CMCNs are capable of interacting with the complicated biological milieu of the tumor because they contain the signaling networks and intrinsic functions of their parent cells. Numerous cell membranes have been investigated for the purpose of masking nanocarriers with membranes, and various tumor-targeting methods have been devised to improve cancer targeted chemotherapy. Moreover, the diverse structure of the membrane from different cell sources broadens the spectrum of CMCNs and offers an entirely new class of drug-delivery systems. Aim of review This review will describe the manufacturing processes for CMCNs and the therapeutic uses for different kinds of cell membrane-coated nanocarrier-based drug delivery systems, as well as addressing obstacles and future prospects. Graphical Abstract
High-mobility group box 1 (HMGB1) functions as a proinflammatory cytokine and is one of the most intriguing molecules in inflammatory disorders and cancers. Notably, HMGB1 is a potential therapeutic target and novel biomarker in related diseases. However, the diagnostic value of HMGB1 for benign and malignant asbestos-related diseases (ARDs) remains unclear. In this work, we detected preoperative serum HMGB1 levels in Chinese asbestos-exposed (AE) and ARDs populations and further evaluated the diagnostic value of HMGB1 in patients with certain types of ARDs, including those with pleural plaques, asbestosis, or malignant mesothelioma (MM). The experimental data presented that the serum level of HMGB1 was significantly elevated in AE and ARDs subjects. Our findings indicated that serum HMGB1 is a sensitive and specific biomarker for discriminating asbestosis- and MM-affected individuals from healthy or AE individuals. In addition, serum matrix metalloproteinases 2 and 9 are not correlated with HMGB1 in ARDs. Thus, our study provides supporting evidence for HMGB1 as a potential biomarker either for the clinical diagnosis of high-risk AE cohorts or for evaluating ARDs.
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death, partly due to the high recurrence rates for patients with PDAC. Current postoperative surveillance methods, including monitoring of clinical symptoms, tumor markers, and CT imaging, lack sensitivity and specificity for minimal residual disease (MRD). We investigated whether the detection of circulating tumor DNA (ctDNA) could identify MRD and predict relapse in postoperative patients with PDAC. In this study, we performed panel-captured sequencing to detect somatic mutations. Matched tissue samples were obtained to verify mutation. A total of 27 patients and 65 plasma samples were included. Among the somatic mutations, KRAS and TP53 were the most recurrent genes in both tissue and plasma samples. The detectable rate of ctDNA increased with the stage of PDAC. The maximal variant allele fraction (VAF) of ctDNA had a positive correlation with tumor largest diameter (p = 0.0101). Patients with ctDNA-positive status postoperatively had a markedly reduced disease-free survival (DFS) compared to those with ctDNA-negative status (HR, 5.20; p = 0.019). Positive vascular invasion significantly influenced disease-free survival (DFS) (p = 0.036), and positive postoperative ctDNA status was an independent prognostic factor for DFS (HR = 3.60; 95% CI, 1.15-11.28; p = 0.028). Postoperative ctDNA detection provides strong evidence of MRD and identifies patients with a high risk of relapse. ctDNA detection is a promising approach for personalized patient management during postoperative follow-up.
of HIF-1α and VEGF. The mean survival time and the 5-year survival rate in cases with positive expression HIF-1α and VEGF and MVD value ≥ 41.5/0.72 mm 2 were significantly lower than those with negative expression of HIF-1α and VEGF and MVD value < 41.5/0.72 mm 2 . CONCLUSION:Overexpression of HIF-1α is found in gastric carcinoma. HIF-1α may induce the angiogenesis in gastric carcinoma by upregulating the transcription of VEGF gene, and take part in tumor invasion and metastasis. They can be used as prognostic markers of gastric cancer in clinical practice. INTRODUCTIONAngiogenesis plays an important role in tumor growth and metastasis [1,2] . The formation of tumor microvessels is stimulated by angiogenic factors, especially vascular endothelial growth factor (VEGF) [3][4][5] . Hypoxia is related to tumor cell growth, differentiation, invasion and metastasis activity. In recent years, studies showed that hypoxia inducible factor-1 (HIF-1) played an important role in oxygen balance and tumor angiogenesis [6] . HIF-1 consists of α and β subunits, and HIF-1α is a key subunit of HIF activity regulated by hypoxia [1] . HIF-1 mRNA and protein overexpression was found in a variety of tumors, including breast cancer, prostate cancer, kidney cancer, rectal adenocarcinoma, etc [2,4,[7][8][9] . However, research on HIF-1α in gastric cancer was rarely reported. In the present study, BASIC RESEARCHUpregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma Abstract AIM:To investigate the implication of the hypoxia inducible factor HIF-1α mRNA in gastric carcinoma and its relation to the expression of vascular endothelial growth factor (VEGF) protein, tumor angiogenesis invasion/metastasis and the patient's survival. METHODS:In situ hybridization was used to examine expression of HIF-1α mRNA, and immunohistochemical staining was used to examine expression of VEGF protein and CD34 in 118 specimens from patients with gastric carcinoma. RESULTS:The positive rates of HIF-1α mRNA and VEGF protein were 49.15% and 55.92%, respectively. Positive expressions of HIF-1α and VEGF in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis were dramatically stronger than stage T1-T2 cases and those without vessel invasion, lymph node metastasis and distant metastasis. The mean microvascular density (MVD) in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis was significantly higher than stage T1-T2 tumors and those without vessel invasion, lymph node metastasis and distant metastasis. The mean MVD in tumors with positive HIF-1α and VEGF expression was significantly higher than that in tumors with negative HIF-1α and VEGF expression. The expression of HIF-1α was positively correlated with VEGF protein. There were positive correlations between MVD and expression
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