{"id":75530,"date":"2025-09-20T16:14:09","date_gmt":"2025-09-20T16:14:09","guid":{"rendered":"https:\/\/www.europesays.com\/ie\/75530\/"},"modified":"2025-09-20T16:14:09","modified_gmt":"2025-09-20T16:14:09","slug":"reticulocalbin-1-in-clear-cell-renal-cell-carcinoma-clinical-and-functional-evidence-for-its-role-as-a-biomarker-and-potential-therapeutic-target-bmc-cancer","status":"publish","type":"post","link":"https:\/\/www.europesays.com\/ie\/75530\/","title":{"rendered":"Reticulocalbin-1 in clear cell renal cell carcinoma: clinical and functional evidence for its role as a biomarker and potential therapeutic target | BMC Cancer"},"content":{"rendered":"

Despite therapeutic advancements, the prognosis for metastatic ccRCC remains poor, with a 5-year survival rate of approximately 12\u201320 % [25<\/a>]. Prognostic models, such as the International Metastatic RCC Database Consortium (IMDC) criteria, help stratify patients based on risk factors, guiding treatment selection and predicting survival outcomes [5<\/a>]. To improve the outcomes in advanced ccRCC, ongoing clinical trials and basic research continue to focus on biomarker-driven therapies and the discovery of novel targets and treatment combinations.<\/p>\n

Our study focuses on RCN1 and its role in ccRCC, deciphering also the mechanisms involved in cancer progression.<\/p>\n

RCN1 is a Ca2+\u2009-binding protein, involved in endoplasmic reticulum stress, highly expressed in several malignant tumors like breast cancer, colorectal cancer, naso-pharyngeal carcinoma or non-small cell lung carcinoma [11<\/a>, 17<\/a>, 26<\/a>, 27<\/a>] associated either with poor prognosis or therapy resistance. The role of RCN1 in ccRCC is mainly unknown.<\/p>\n

For our investigations, we asked first if RCN1 could be found at high levels ccRCC. Therefore, we interrogated the CTPAC data set and performed additional immunohistochemistry on a TMA comprising 306 patients. As described in previous publications [11<\/a>, 17<\/a>, 26<\/a>, 27<\/a>], RCN1 has a high expression in many solid tumors, but among all solid tumors, ccRCC has the highest RCN1 level compared with non-neoplastic tissue. We confirmed the results in the immunohistochemistry analysis, the majority of tumors express reticulocalbin-1. This also confirms the proteomics analysis published by Giribaldi et al. [20<\/a>], who described an RCN1 overexpression in 21 out of 24 investigated ccRCC specimens.<\/p>\n

Alteration of gene expression, either up- or downregulation, does not necessarily correlate with the protein level. Therefore, we analyzed the TCGA data set and demonstrated a high RCN1 expression in tumors compared with non-neoplastic tissue, in concordance with the protein data.<\/p>\n

A high level of RCN1 was associated with poor clinicopathological parameters, like high grading or high tumor stage. The association between high levels of RCN1 and prognostic infaust parameters was also described in non-small cell lung carcinoma (NSCLC) and esophageal squamous carcinoma [11<\/a>, 28<\/a>].<\/p>\n

Overexpression of RCN1 and high levels of RCN1 correlate with shorter overall survival in ccRCC, which is in line with the results published for NSCLC and esophageal squamous carcinoma [11<\/a>, 28<\/a>]. Experiments in NSCLC and esophageal squamous carcinoma also revealed a significant decrease in invasion and migration after RCN1 knockdown [11<\/a>, 28<\/a>]. In our experiments, the Caki-1 ccRCC cell line showed a significant difference in migration and invasion potential compared to our control. For the A498 cell line (p\u2009=\u20090.0583), there is a tendency towards lower migration in the knock-down cell line but no detectable effect on the invasion. A possible explanation for the differences between the cell lines may lie in the biological characteristics of the A498 cells. A498 behaves far more aggressively regarding cell proliferation, migration and invasion. Moreover, A498 is derived from a primary tumor harboring a VHL mutation, while Caki-1 is a VHL wild type metastatic ccRCC cell line. Due to the VHL mutation, A498 cells may compensate for or mask the effects of RCN1 knockdown, as this mutation leads to constitutive activation of HIF. HIF induces the expression of growth factors that activate the PI3K\/AKT pathway \u2013 an established driver of cell migration and invasion [29<\/a>]. Different origins and mutational statuses can lead to distinct biological behaviors.<\/p>\n

While we were able to show effects on cell motility using knockdown experiments, the pathomechanistic pathway remains unclear. Although the pathway related to apoptosis inhibition has already been investigated using HEK- and A498-cells [16<\/a>], the mechanisms behind cell movement influenced by RCN1 are yet unknown. This limitation will be addressed in a follow-up study.<\/p>\n

We also have to acknowledge a possible influence of tumor environment, e.g. the influence of regulatory T-cells on ccRCC and its interaction with RCN1 [21<\/a>], which cannot be examined in a cell-line model. In addition to the influence of CD4-positive T-cells, we analyzed a possible influence of cytotoxic T-cells (CD8+) and macrophages in the tumor area. From squamous carcinoma (esophageal and oral) is known that the knockdown of RCN1 inhibits the polarization of M2 macrophages [28<\/a>, 30<\/a>]. We have chosen another approach and quantified the macrophages and the clusters of macrophages by immunohistochemistry. The presence of macrophage clusters showed a tendency to high RCN1 expression (p\u2009=\u20090.051), but our cohort did not show any correlation between the macrophage infiltration, RCN1 expression and clinical outcome. However, in our experiment, we did not differentiate between M1 and M2 macrophages, since CD68 could be a marker for both subtypes. To confirm that the effect described by Guo et al. does not occur in ccRCC, a differentiation between the types of macrophages should be addressed in further studies. Additionally, we couldn\u2019t notice any significant correlation between CD8 T-lymphocyte infiltration and a high RCN1 level in ccRCC, so we couldn\u2019t confirm the results published by Qixin et al. [21<\/a>], who discovered an association of RCN1 with Tregs across malignant tumors, including ccRCC. Our results show no correlation between macrophages and cytotoxic lymphocytes infiltration and RCN1 levels in ccRCC.<\/p>\n

The expression of RCN1 is very low in normal tissue but often high in ccRCC tumor cells, which predisposes it as a possible therapeutic target. RCN1 has been reported to induce resistance to sorafenib (TKI-class) by inhibiting ER stress-induced apoptosis in HCC [18<\/a>]. As the TKI-class is also used as one of the main therapeutic options in ccRCC, a similar mechanism in ccRCC could indicate RCN1 suppression to be a promising addition to TKI-based therapies. This possibility requires further investigation. Another possible therapeutic approach is to use the high expression of reticulocalbin-1 as a target for an antibody\u2013drug-conjugate, benefiting from the homogenous distribution in all tumor cells. A previous study by Fukuda et al. [9<\/a>] described the RCN1 expression across non-malignant and malignant tissues. RCN1 is highly expressed in few glands especially in the gonads, tissues with terminal differentiation like muscle cells and neurons, and activated fibroblasts in inflammatory tissue as well as in tumor surrounding tissue. Almost no RCN1 expression was detected in kidney tissue and many endocrine glands, like thyroid gland or hypophysis, and only low expression was found in organs of the gastrointestinal system. These findings suggest that potential adverse effects may primarily affect the gonads and the central nervous system, but because chemotherapeutics usually target cell proliferation, it could be possible that the effect on neurons is limited. Although the RCN1 expression is relatively low in proliferative tissues, it is still present in many of them, suggesting that chemotherapeutics could have a stronger effect in these tissues. Nevertheless, these considerations are hypothetical and further research in this field needs to be done to assess target selectivity and tissue-specific toxicity.<\/p>\n

Considering these aspects, we propose that RCN1 can be used to complement existing biomarkers by offering additional prognostic insight and therapeutic relevance. While VHL mutations leading to elevated CAIX expression by stabilizing HIF present hallmarks of ccRCC [31<\/a>], RCN1 distinguishes itself by being involved in ER stress related and secretory pathways, suggesting a role apart from the hypoxia pathway or mutations in chromatin remodeling like BAP1 or PBRM1\u00a0[32<\/a>]. Additionally, as RCN1 is implicated in cancer biology beyond ccRCC, further investigation may offer novel therapeutic insight and accelerate drug development.<\/p>\n","protected":false},"excerpt":{"rendered":"Despite therapeutic advancements, the prognosis for metastatic ccRCC remains poor, with a 5-year survival rate of approximately 12\u201320…\n","protected":false},"author":2,"featured_media":75531,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[77],"tags":[15596,2564,2566,51306,18,910,2100,19,17,7482,51307,111,133,51309,5591,51308],"class_list":{"0":"post-75530","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-science","8":"tag-biomarker","9":"tag-biomedicine","10":"tag-cancer-research","11":"tag-clear-cell-renal-cell-carcinoma","12":"tag-eire","13":"tag-general","14":"tag-health-promotion-and-disease-prevention","15":"tag-ie","16":"tag-ireland","17":"tag-medicine-public-health","18":"tag-n-rcn1n","19":"tag-oncology","20":"tag-science","21":"tag-surgical-oncology","22":"tag-survival","23":"tag-target-identification"},"share_on_mastodon":{"url":"","error":""},"_links":{"self":[{"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/posts\/75530","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/comments?post=75530"}],"version-history":[{"count":0,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/posts\/75530\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/media\/75531"}],"wp:attachment":[{"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/media?parent=75530"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/categories?post=75530"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.europesays.com\/ie\/wp-json\/wp\/v2\/tags?post=75530"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}