Reticulocalbin-1 (RCN1) is a calcium-binding protein primarily located in the endoplasmic reticulum (ER) lumen, with six conserved regions that play a crucial role in maintaining intracellular homeostasis. Its functions include regulation of cell proliferation and apoptosis, and it has been implicated in the development of various tumors. Studies have shown that RCN1 is upregulated in tumor tissues compared to normal tissues, and its expression level is closely associated with poor prognosis in various types of cancer, including oral squamous cell carcinoma (OSCC) [1], esophageal squamous cell carcinoma (ESCC) [2], non-small cell lung cancer (NSCLC) [5], and hepatocellular carcinoma (HCC) [6].

In OSCC, RCN1 knockdown has been shown to inhibit the proliferation, migration, and invasion of tumor cells, as well as the M2 polarization of tumor-associated macrophages (TAMs) [1]. Similarly, in ESCC, downregulation of RCN1 significantly inhibited the migration, invasion, and epithelial-mesenchymal transition (EMT) of tumor cells, and promoted cell apoptosis, while also inhibiting M2 polarization [2]. In NSCLC, high expression of RCN1 was associated with poor prognosis, and RCN1 knockdown suppressed cell proliferation, migration, and invasion [5]. In HCC, RCN1 was significantly upregulated in sorafenib-resistant cells, promoting tumor progression and activating the IRE1α-XBP1s pathway, which is required for c-MYC signaling [6].

Furthermore, RCN1 has been identified as a potential diagnostic and prognostic indicator in OSCC [1], ESCC [2], and glioblastoma (GBM) [7]. In GBM, a bioinformatics analysis identified RCN1 as one of the key genes involved in poor prognosis, and its expression was positively correlated with other prognostic markers [7]. Additionally, salivary levels of RCN1 have been shown to be significantly higher in OSCC patients compared to healthy controls, suggesting its potential as a screening test for OSCC [9].

The mechanism by which RCN1 promotes tumor progression and poor prognosis is not fully understood, but studies have suggested that it may involve regulation of calcium homeostasis, ER stress-induced apoptosis, and activation of oncogenic pathways. Inhibition of RCN1 has been shown to promote pyroptosis in acute myeloid leukemia (AML) cells through caspase-1 and gasdermin D (GSDMD) signaling [3]. RCN1 also suppresses ER stress-induced apoptosis via calcium homeostasis and PERK-CHOP signaling [8].

In conclusion, RCN1 is a multifunctional protein that plays a significant role in maintaining intracellular homeostasis and regulating cell proliferation and apoptosis. Its upregulation in various types of cancer suggests a potential role in tumor progression and poor prognosis. Further research is needed to fully understand the mechanisms by which RCN1 functions in cancer and to explore its potential as a therapeutic target for cancer treatment.

References:

1. Liu, Han, Guo, Haiyang, Wu, Yuehan, Zhao, Runzhe, Liu, Ying. 2023. RCN1 deficiency inhibits oral squamous cell carcinoma progression and THP-1 macrophage M2 polarization. In Scientific reports, 13, 21488. doi:10.1038/s41598-023-48801-2. https://pubmed.ncbi.nlm.nih.gov/38057406/

2. Guo, Haiyang, Shu, Jinghao, Hu, Guangbing, Yin, Yaolin, Wang, Xianfei. 2024. Downregulation of RCN1 inhibits esophageal squamous cell carcinoma progression and M2 macrophage polarization. In PloS one, 19, e0302780. doi:10.1371/journal.pone.0302780. https://pubmed.ncbi.nlm.nih.gov/38713738/

3. Deng, Sisi, Pan, Yuming, An, Na, Du, Xin, Zhang, Qiaoxia. 2023. Downregulation of RCN1 promotes pyroptosis in acute myeloid leukemia cells. In Molecular oncology, 17, 2584-2602. doi:10.1002/1878-0261.13521. https://pubmed.ncbi.nlm.nih.gov/37746742/

4. Takasaki, Teruaki, Bamba, Asuka, Kukita, Yuka, Ishihara, Keiichi, Sugiura, Reiko. 2024. Rcn1, the fission yeast homolog of human DSCR1, regulates arsenite tolerance independently from calcineurin. In Genes to cells : devoted to molecular & cellular mechanisms, 29, 589-598. doi:10.1111/gtc.13122. https://pubmed.ncbi.nlm.nih.gov/38715219/

5. Chen, Xinming, Shao, Weiwei, Huang, Hua, Yao, Sumei, Ke, Honggang. 2018. Overexpression of RCN1 correlates with poor prognosis and progression in non-small cell lung cancer. In Human pathology, 83, 140-148. doi:10.1016/j.humpath.2018.08.014. https://pubmed.ncbi.nlm.nih.gov/30172915/

6. Wang, Jia-Wei, Ma, Li, Liang, Yuan, Zhu, Ya-Qing, Wang, Bao-Lin. 2021. RCN1 induces sorafenib resistance and malignancy in hepatocellular carcinoma by activating c-MYC signaling via the IRE1α-XBP1s pathway. In Cell death discovery, 7, 298. doi:10.1038/s41420-021-00696-6. https://pubmed.ncbi.nlm.nih.gov/34663798/

7. Yin, Xiaofeng, Wu, Quansheng, Hao, Zheng, Chen, Laizhao. 2022. Identification of novel prognostic targets in glioblastoma using bioinformatics analysis. In Biomedical engineering online, 21, 26. doi:10.1186/s12938-022-00995-8. https://pubmed.ncbi.nlm.nih.gov/35436915/

8. Xu, S, Xu, Y, Chen, L, Chen, J, Teng, J. 2017. RCN1 suppresses ER stress-induced apoptosis via calcium homeostasis and PERK-CHOP signaling. In Oncogenesis, 6, e304. doi:10.1038/oncsis.2017.6. https://pubmed.ncbi.nlm.nih.gov/28319095/

9. Ueda, Sei, Hashimoto, Kengo, Miyabe, Satoru, Nagao, Toru, Nomoto, Shuji. . Salivary NUS1 and RCN1 Levels as Biomarkers for Oral Squamous Cell Carcinoma Diagnosis. In In vivo (Athens, Greece), 34, 2353-2361. doi:10.21873/invivo.12048. https://pubmed.ncbi.nlm.nih.gov/32871760/