Minyu Zhou

XB130 promotes proliferation and invasion of gastric cancer cells

BackgroundXB130 has been reported to be expressed by various types of cells such as thyroid cancer and esophageal cancer cells, and it promotes the proliferation and invasion of thyroid cancer cells. Our previous study demonstrated that XB130 is also expressed in gastric cancer (GC), and that its expression is associated with the prognosis, but the role of XB130 in GC has not been well characterized.MethodsIn this study, we investigated the influence of XB130 on gastric tumorigenesis and metastasis in vivo and in vitro using the MTT assay, clonogenic assay, BrdU incorporation assay, 3D culture, immunohistochemistry and immunofluorescence. Western blot analysis was also performed to identify the potential mechanisms involved.ResultsThe proliferation, migration, and invasion of SGC7901 and MNK45 gastric adenocarcinoma cell lines were all significantly inhibited by knockdown of XB130 using small hairpin RNA. In a xenograft model, tumor growth was markedly inhibited after shXB130-transfected GC cells were implanted into nude mice. After XB130 knockdown, GC cells showed a more epithelial-like phenotype, suggesting an inhibition of the epithelial-mesenchymal transition (EMT) process. In addition, silencing of XB130 reduced the expression of p-Akt/Akt, upregulated expression of epithelial markers including E-cadherin, α-catenin and β-catenin, and downregulated mesenchymal markers including fibronectin and vimentin. Expression of oncoproteins related to tumor metastasis, such as MMP2, MMP9, and CD44, was also significantly reduced.ConclusionsThese findings indicate that XB130 enhances cell motility and invasiveness by modulating the EMT-like process, while silencing XB130 in GC suppresses tumorigenesis and metastasis, suggesting that it may be a potential therapeutic target.

Theranostic pH-sensitive nanoparticles for highly efficient targeted delivery of doxorubicin for breast tumor treatment

A multifunctional theranostic nanoplatform integrated with environmental responses has been developed rapidly over the past few years as a novel treatment strategy for several solid tumors. We synthesized pH-sensitive poly(β-thiopropionate) nanoparticles with a supermagnetic core and folic acid (FA) conjugation (FA-doxorubicin-iron oxide nanoparticles [FA-DOX@ IONPs]) to deliver an antineoplastic drug, DOX, for the treatment of folate receptor (FR)-overexpressed breast cancer. In addition to an imaging function, the nanoparticles can release their payloads in response to an environment of pH 5, such as the acidic environment found in tumors. After chemical (1H nuclear magnetic resonance) and physical (morphology and super-magnetic) characterization, FA-DOX@IONPs were shown to demonstrate pH-dependent drug release profiles. Western blotting analysis revealed the expression of FRs in three breast cancer cell lines, MCF-7, BT549, and MD-MBA-231. The cell counting kit-8 assay and transmission electron microscopy showed that FA-DOX@IONPs had the strongest cytotoxicity against breast cancer cells, compared with free DOX and non-FR targeted nanoparticles (DOX@IONPs), and caused cellular apoptosis. The FA-DOX@IONP-mediated cellular uptake and intracellular internalization were clarified by fluorescence microscopy. FA-DOX@IONPs plus magnetic field treatment suppressed in vivo tumor growth in mice to a greater extent than either treatment alone; furthermore, the nanoparticles exerted no toxicity against healthy organs. Magnetic resonance imaging was successfully applied to monitor the nanoparticle accumulation. Our results suggest that theranostic pH-sensitive nanoparticles with dual targeting could enhance the available therapies for cancer.

MACC1 decreases the chemosensitivity of gastric cancer cells to oxaliplatin by regulating FASN expression

The effect of chemotherapeutic agents is limited as a result of drug resistance, which demands prompt solutions provided by clinical studies. To date, the underlying mechanisms of chemotherapy resistance are relatively unknown. Metastasis-associated in colon cancer 1 (MACC1) is an oncogene associated with the progression and prognosis of gastric cancer (GC). Bioinformatic analysis revealed that MACC1 is positively associated with fatty acid synthase (FASN), a major enzyme of lipogenesis, and drives chemoresistance to oxaliplatin in GC. Similar findings were demonstrated in two GC cell lines (BGC-823 and MKN-28) with MACC1 ectopic expression. We next employed FASN inhibitor C75 or siFASN (small interfering RNA targeted to FASN) to block endogenous fatty acid metabolism and it was revealed that cell proliferation and chemoresistance to oxaliplatin induced by MACC1 upregulation were attenuated by FASN blockade to various extents. Conclusively, these outcomes highlight a novel role of MACC1 in GC cell lipogenesis, and suggest that MACC1 may be an attractive target to decrease oxaliplatin resistance in GC.

Impact of liver tumor percutaneous radiofrequency ablation on circulating tumor cells

Radiofrequency ablation has become an increasingly common therapeutic technique for patients with hepatocellular carcinoma or metastatic liver tumors. However, reports on the effect of percutaneous radiofrequency ablation (PRFA) on circulating tumor cells (CTCs) are limited. The present study aimed to further investigate the impacts of PRFA on the numbers and phenotypes of CTCs in patients with hepatocellular carcinoma or metastatic liver tumors. A total of 43 patients with hepatocellular carcinoma or 7 types of metastatic liver tumors were treated with PRFA. A total of 5 ml blood per sample were collected from the peripheral circulation 30 min before and 3 days after PRFA. The total number of CTCs significantly increased 3 days after PRFA, and the mesenchymal phenotype CTCs, which also increased significantly, significantly contributed to the overall increase in CTCs. Furthermore, the lymphocyte levels were significantly decreased following PRFA, and the CTC level was significantly higher in patients with decreased lymphocyte levels compared with those with increased lymphocyte levels. Liver tumor PRFA may increase the level of mesenchymal phenotype CTCs, which is significantly associated with the lymphocyte count. Factors pertaining to the performance of PRFA were also investigated in the present research, but no significant results were identified.

Inhibition of SLC1A5 sensitizes colorectal cancer to cetuximab: SLC1A5 inhibition enhances the efficacy of cetuximab

Cetuximab resistance is a key barrier in treating metastatic colorectal cancer (mCRC). Targeting of metabolic resources import could resensitize drug‐resistant cancer cells to anticancer treatments. Here we showed that the expression of the glutamine transporter solute carrier 1 family member 5 (SLC1A5) in clinical CRC samples of patients resisted to cetuximab was significantly higher than in those of patients responded to cetuximab. Inhibition of SLC1A5 by shRNA‐mediated gene silencing or pharmacological inhibitor significantly suppressed the growth of CRC. Moreover, inhibition of SLC1A5 significantly enhanced the inhibitory efficacy of cetuximab on CRC proliferation both in vitro and in vivo. Mechanistically, SLC1A5 inhibition facilitated EGFR degradation through the ubiquitin‐proteasome pathway, and decreased the expression of nuclear EGFR, both of which might have contribution to the improved response to cetuximab. This study provides the metabolic molecule SLC1A5 as a potential therapeutic target to increase the efficacy of cetuximab on CRC.

686PDLC1 DETERMINES THE EFFICIENCY OF FLUOROPYRIMIDINE AND OXALIPLATIN REGIMEN IN GASTRIC CANCER ADJUVANT CHEMOTHERAPY

ABSTRACT Aim: The Rho-GTPase-activating protein Deleted in liver cancer (DLC1) is recently known as a tumor suppressor and deficient in gastric cancer (GC) cells. However, the prognostic value of DLC1 in GC is still unclear. On the other hand, fluoropyrimidine and oxaliplatin (FP-LOHP) regimen is wildly used for GC adjuvant chemotherapy, but no reliable marker has been found to determine the efficiency of this regimen. Methods: From 2004 to 2014, we retrospectively followed 251 Stage IB-III patients with radical resection. All patients received adjuvant chemotherapy with or without FP-LOHP. The DLC1 expression of in GC and their para-cancerous tissues was detected by immunohistochemical staining. The pathological factors, including time to recurrence (TTR) and overall survival time (OS), were analyzed. Results: DLC1 was lowly expressed in most (185/251) GC samples compared to normal mucosa. Lower expression of DLC1 indicated larger tumor size, more advanced TNM stage, deeper tumor invasion, and more lymph node metastasis. On the contrary, relatively higher DLC1 expression demonstrated longer TTR (HR 2.232; 95% CI 1.295-3.857; P = 0.004) and OS (HR 2.910; 95% CI 1.543-5.488; P = 0.001). Patients applying FP-LOHP as adjuvant chemotherapy are less likely to suffer GC recurrence than those used other therapies. However, only the DLC1 positive GC patients receiving FP-LOHP [DLC1(+)/FP-LOHP(+)] showed more favorable TTR and OS than DLC1(-)/FP-LOHP(+) (TTR, k2 = 26.364, P DCL1 FP-LOHP Total (%) TTR (month) Median (95% CI) 3-yr non-recurrence (%) OS (month) Median (95% CI) 5-yr survival (%) + + 13.9 / 89.6 / 74.5 + - 12.4 37 (25.8-48.2) 51.4 / 58.6 - + 27.5 27 (21.6-32.4) 32.9 51 (33.2-68.8) 16.7 - - 46.2 22 (14.3-29.7) 23.3 36 (32.4-39.6) 28.2 Conclusions: Low expression of DLC1 is correlated with GC progression and predicts high risk of recurrence and mortality. Only the DLC1 positive patients may benefit from FP-LOHP as adjuvant chemotherapy in GC. Disclosure: All authors have declared no conflicts of interest.