Reticulocalbin 1 (RCN1), an endoplasmic reticulum (ER)‐resident Ca2+‐binding protein, is dysregulated in cancers, but its pathophysiological roles are largely unclear. Here, we demonstrate that RCN1 is overexpressed in clinical prostate cancer (PCa) samples, associated with cyclin B, not cyclin D1 expression, compared to that of benign tissues in a Chinese Han population. Downregulation of endogenous RCN1 significantly suppresses PCa cell viability and arrests the cell cycles of DU145 and LNCaP cells at the S and G2/M phases, respectively. RCN1 depletion causes ER stress, which is evidenced by induction of GRP78, activation of PERK and phosphorylation of eIF2α in PCa cells. Remarkably, RCN1 loss triggers DU145 cell apoptosis in a caspase‐dependent manner but mainly causes necroptosis in LNCaP cells. An animal‐based analysis confirms that RCN1 depletion suppresses cell proliferation and promotes cell death. Further investigations reveal that RCN1 depletion leads to elevation of phosphatase and tensin homolog (PTEN) and inactivation of AKT in DU145 cells. Silencing of PTEN partially restores apoptotic cells upon RCN1 loss. In LNCaP cells, predominant activation of CaMKII is important for necroptosis in response to RCN1 depletion. Thus, RCN1 may promote cell survival and serve as a useful target for cancer therapy.

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Background and aim: Mesenchymal stem cells (MSCs) are capable of impacting tumor progression but its role in tumor stroma remodeling still remains unclear. This present study was aimed to evaluate the potential function of MSCs on tumor stroma remodeling using rabbits VX2 bladder tumor model.Methods: The VX2 bladder tumor models were established by injecting mixed cell suspensions (106 of VX2 tumor cells and 0/106/107 of autologous MSCs in group A, B, C, respectively) into the bladder mucosa using thirty male New Zealand white rabbits. The tumor volume was measured by ultrasound at the time points of 1st, 2nd, 3rd and 4th week after inoculation. At the end of the fourth week, the tumor tissue expressions of basic fibroblast growth factor (bFGF), transforming growth factor beta 1 (TGFβ-1), hepatocyte growth factor (HGF), matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) were determined using Real-time quantitative PCR and immunohistochemistry. Masson trichrome staining and Cy3-FITC double-labelled immunofluorescence staining were used to determine the MSCs distribution in tumor tissue in another two rabbits implanted with a cell suspension of 106 VX2 tumor cells and 106 autologous MSCs.Results: MSCs were homogeneously distributed in tumor tissues after 7 days of inoculation, which were not consistent with the distribution of tumor stroma. After 21 days of inoculation, MSCs have been integrated into tumor interstitial tissue and mainly distributed in the mesenchyma around the tumor nest. At the 1st, 2nd, 3rd and 4th week time point, tumor volume in group A < group B < group C, and the difference has statistical significance (all p<0.001).The relative mRNA and protein levels of bFGF, TGFβ-1 and HGF were significantly higher in group B and C compared with group A (all p<0.05), as well as the mRNA levels of bFGF, HGF were higher in group C than group B (p<0.05), and the protein levels of bFGF, TGFβ-1 were higher in group C than group B (p<0.05). The mRNA and protein levels of MMP2 were significantly higher in group B, C than group A (p<0.05). MMP9 was increasingly over expressed along with the growing amount of MSCs inoculated within tumor, both at the level of mRNA and protein (all p<0.05).Conclusion: MSCs participate in tumor stroma remodeling via inducing overexpression of some important growth factors and MMPs.

Receptor tyrosine kinase (RTK) inhibitors, such as sunitinib and sorafenib, remain the first-line drugs for the treatment of mRCC. Acquired drug resistance and metastasis are the main causes of treatment failure. However, in the case of metastasis Renal Cell Cancer (mRCC), which showed a good response to sunitinib, we found that long-term treatment with sunitinib could promote lysosome biosynthesis and exocytosis, thereby triggering the metastasis of RCC. By constructing sunitinib-resistant cell lines in vivo, we confirmed that TFE3 plays a key role in the acquired resistance to sunitinib in RCC. Under the stimulation of sunitinib, TFE3 continued to enter the nucleus, promoting the expression of endoplasmic reticulum (ER) protein E-Syt1. E-Syt1 and the lysosomal membrane protein Syt7 form a heterodimer, which induces ER fragmentation, Ca2+ release, and lysosomal exocytosis. Lysosomal exocytosis has two functions: pumping sunitinib out from the cytoplasm, which promotes resistance to sunitinib in RCC, releasing cathepsin B (CTSB) into the extracellular matrix (ECM), which can degrade the ECM to enhance the invasion and metastasis ability of RCC. Our study found that although sunitinib is an effective drug for the treatment of mRCC, once RCC has acquired resistance to sunitinib, sunitinib treatment will promote metastasis.