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PURPOSE: As the first-line drug for treatment of HER2-positive metastatic gastric cancer (GC), Herceptin exhibits significant therapeutic efficacy. However, acquired resistance of Herceptin limits the therapeutic benefit of gastric cancer patients, in which the molecular mechanisms remain to be further determined. METHODS: Quantitative real-time polymerase chain reaction was performed to detect the mRNA levels of ARPP-19 and CD44 in GC cells. Protein levels were determined using Western blot and IHC staining. MTT and soft agar colony formation assays were used to measure cell proliferation. Xenograft model was established to verify the functional role of ARPP-19 in Herceptin resistance in vivo. Sphere formation assay was conducted to determine cell stemness. RESULTS: We observed ARPP-19 was up-regulated in Herceptin resistance gastric cancer cells NCI-N87-HR and MKN45-HR. The forced expression of ARPP-19 promoted, whereas the silencing of ARPP-19 impaired Herceptin resistance of HER2-positive gastric cancer cells both in vitro and in vivo. Moreover, ARPP-19 significantly enhanced the sphere formation capacity and CD44 expression, CD44 was also a positive factor of Herceptin resistance in HER2-positive gastric cancer cells. In addition, high level of ARPP-19 was positively associated with Herceptin resistance and poor survival rate of gastric cancer patients. CONCLUSION: We have demonstrated that ARPP-19 promoted Herceptin resistance of gastric cancer via up-regulation of CD44, our study suggested that ARPP-19 could be a potential diagnostic and therapeutic candidate for HER2-positive gastric cancer.
RESUMO
OBJECTIVE: To explore the regulation and clinical significance of intestinal dripping of Jianpi Tongli (JPTL) Chinese herbs on levels of serum cytokines, such as interleukin-2 (IL-2), soluble interleukin-2 receptor (sIL-2R) and interleukin-12 (IL-12) in treating patients with gastric cancer (GC) at early post-operational stage. METHODS: Sixty patients with GC were randomly divided into two groups, i. e. the studied group (n = 30), treated with JPTL Chinese herbs, and the control group (n = 30) treated with normal saline. The medication was started from the 1st day after operation by intestinal dripping daily, 7 days as one course. Levels of IL-2, sIL-2R and IL-12 were observed before and after operation. RESULTS: Significant difference was seen on the 7th day post-operation between the studied and the control group, mainly in aspects of obvious increase of IL-2 and decrease of sIL-2R (P <0.05), no significant difference in IL-12 was found (P >0.05) though there was certain improvement. Compared with pre-operation of the same group, significant difference was found in the studied group in the increased IL-2 and IL-12 and decreased sIL-2R on the 7th day post-operation, while no significant difference in these indexes was found in the control group (P >0.05), though certain improvement was shown. CONCLUSION: Early intestinal dripping of JPTL Chinese herbs to post-operational patients with GC could improve their immune function, which was of important significance in early preventing the severe complications, improving the prognosis, and elevating the survival rate.
