<p>ARPP-19 Mediates Herceptin Resistance via Regulation of CD44 in Gastric Cancer</p>

Abstract

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.

Resistance mechanisms to HER2-targeted therapy in gastroesophageal adenocarcinoma: A systematic review

“…In addition, CD44 and its upstream regulator cAMP-regulated phosphoprotein 19 (ARPP-19) were upregulated in HER2-positive gastric cancer tissues resistant to trastuzumab. Increased ARPP-19 was also linked to secondary trastuzumab resistance in patients and correlated to lower OS [95]. In contrast, Yu et al reported that upregulation of CD44 in trastuzumab resistant cells is correlated with favorable OS [97].…”

“…(F) PI3K/AKT and MAPK signaling become activated by overexpression of regulating proteins and mutations in PTEN, PI3K, or Src, maintaining downstream signaling [32,33,36,40,47,53,59,60,63,[66][67][68][69][70][71][72][73][74][75][76][77][78][79]. (G) Induction of EMT by Wnt signaling and TGFβ [28,31,34,52,55,71,[88][89][90], altered cell cycle regulation [45,47,67,[91][92][93], stemness [71,[95][96][97][98][99], metabolic reprogramming [70,98,[105][106][107], and decreased production and increased efflux of DM1…”

“…There is increasing evidence that cancer cells with stem cell-like properties are more resistant to chemotherapy or radiotherapy treatments, due to self-renewal capacity and tumor cell dormancy [87]. Six studies investigated the role of stem cell characteristics in GEA and anti-HER2 drug resistance [71,[95][96][97][98][99]. In trastuzumab resistant NCI-N87 and MKN-45 cells the C-Maf-inducing protein (CMIP) was overexpressed and found to positively regulate SOX2 expression, a stemness transcription factor, promoting secondary resistance to trastuzumab [96].…”

“…Similarly, Gse1 coiled-coil protein (GSE1) overexpression was reported to induce secondary trastuzumab resistance through promoting stem cell behavior [99]. Furthermore, others found that stem cell surface marker CD44 was upregulated and associated with secondary trastuzumab resistance in NCI-N87 and MKN-45 cells [71,95,98]. In addition, CD44 and its upstream regulator cAMP-regulated phosphoprotein 19 (ARPP-19) were upregulated in HER2-positive gastric cancer tissues resistant to trastuzumab.…”