RCN1 induces sorafenib resistance and malignancy in hepatocellular carcinoma by activating c-MYC signaling via the IRE1α–XBP1s pathway

Abstract

The increasing incidence of hepatocellular carcinoma (HCC) is of great concern globally, but the molecular pathogenesis of these tumors remains unclear. Sorafenib is a first-line drug for the treatment of advanced HCC. However, the efficacy of sorafenib in improving patient survival is limited, and most patients inevitably develop resistance to this drug. Recent studies have demonstrated that the activation of the IRE1α–XBP1s pathway might play a protective role in the response to sorafenib and contribute to malignancy in HCC. Here, we found that RCN1, an endoplasmic reticulum resident protein, is significantly upregulated in sorafenib-resistant HCC cells and promotes tumor progression. Our analysis showed that RCN1 may be an independent predictor of tumor recurrence and overall survival. Mechanistically, RCN1 promotes the dissociation of GRP78 from IRE1α in sorafenib-resistant cells by interacting with GRP78 through its EFh1/2 domain. Subsequently, the IRE1α–XBP1s pathway, a branch of the unfolded protein response, is sustainably activated. Interestingly, IRE1α–XBP1s pathway activity is required for c-MYC signaling, one of the most highly activated oncogenic pathways in HCC. These results suggest that RCN1-targeted therapy might be a feasible strategy for the treatment of HCC.

Downregulation of RCN1 promotes pyroptosis in acute myeloid leukemia cells

“…RCN1 has been demonstrated to be highly expressed in a variety of tumor cells and is correlated with patient prognosis in renal cell carcinoma, prostate cancer, glioblastoma, non-small cell lung cancer, oral squamous cell carcinoma, nasopharyngeal cancer, colon cancer, laryngeal cancer, highly aggressive breast cancer, sorafenib-resistant hepatocellular carcinoma cells, and gemcitabine-insensitive human pancreatic adenocarcinoma cells, among others [20][21][22]24,25,27,[55][56][57][58][59][60][61][62][63]. Yoshida et al [64] reported that RCN1 was expressed in lymphatic endothelial cells (T-LECs) and lung cancer cells in lung tumors, but not in lymphatic endothelial cells (N-LECs) in nontumor tissues.…”

“…Reticulocalbin-1 (RCN1), an endoplasmic reticulum protein, plays a crucial role in calcium homeostasis and inhibits ER stress-induced apoptosis [19,20]. In multiple cancers, such as glioblastoma, non-small cell lung cancer, renal cell carcinoma, hepatocellular carcinoma, and oral squamous cell carcinoma, the overexpression of RCN1 has been observed indicating its involvement in tumorigenesis and invasion [21][22][23][24][25]. High levels of RCN1 expression have been associated with sorafenib resistance in hepatocellular carcinoma and doxorubicin resistance in uterine cancer cells [23,26].…”

“…In multiple cancers, such as glioblastoma, non-small cell lung cancer, renal cell carcinoma, hepatocellular carcinoma, and oral squamous cell carcinoma, the overexpression of RCN1 has been observed indicating its involvement in tumorigenesis and invasion [21][22][23][24][25]. High levels of RCN1 expression have been associated with sorafenib resistance in hepatocellular carcinoma and doxorubicin resistance in uterine cancer cells [23,26]. Conversely, downregulation of RCN1 has been found to inhibit cell proliferation and promote cell death by activating the AKT and PTEN pathways in prostate cancer cells [27].…”

Advances of cancer-associated fibroblasts in liver cancer

“…Our previous research showed CAFs secreted HGF to upregulate the expression of cell differentiation (CD)-73, and CD73 positive HCC cells were more resistant to the effects of sorafenib and cisplatin [ 18 ]. Additionally, a recent study by our team showed that CAFs can induce the Reticulocalbin 1 (RCN1) expression in HCC, and high-expressing RCN1 can attenuate the sensitivity of HCC cells to sorafenib via the IRE1α-XBP1s pathway [ 48 ]. Apart from that, chemoresistant HCC cells can also promote CAFs functional enhancement, which in turn provides a more favorable microenvironment for HCC cells to survive.…”

Downregulation of RCN1 inhibits esophageal squamous cell carcinoma progression and M2 macrophage polarization

“…There have been reports of RCN1 protein dysregulation in a variety of diseases, including cardiovascular disease, neuromuscular disease, and tumors (6-8). In recent years, RCN1 has received widespread attention due to its important role in tumorigenesis and progression (9)(10)(11)(12)(13). For example, in prostate cancer cells, downregulation of RCN1 promoted apoptosis and necrosis of cancer cells (13); in non-small cell lung cancer, high expression of the RCN1 protein was found to be signi cantly associated with poor prognosis in non-small cell lung cancer patients, and inhibition of RCN1 was shown to reduce proliferation, migration, and invasion of lung adenocarcinoma cells (12).…”