Stanniocalcin 2 (STC2): a universal tumour biomarker and a potential therapeutical target

Abstract

Stanniocalcin 2 (STC2) is a glycoprotein which is expressed in a broad spectrum of tumour cells and tumour tissues derived from human breast, colorectum, stomach, esophagus, prostate, kidney, liver, bone, ovary, lung and so forth. The expression of STC2 is regulated at both transcriptional and post-transcriptional levels; particularly, STC2 is significantly stimulated under various stress conditions like ER stress, hypoxia and nutrient deprivation. Biologically, STC2 facilitates cells dealing with stress conditions and prevents apoptosis. Importantly, STC2 also promotes the development of acquired resistance to chemo- and radio- therapies. In addition, multiple groups have reported that STC2 overexpression promotes cell proliferation, migration and immune response. Therefore, the overexpression of STC2 is positively correlated with tumour growth, invasion, metastasis and patients' prognosis, highlighting its potential as a biomarker and a therapeutic target. This review focuses on discussing the regulation, biological functions and clinical importance of STC2 in human cancers. Future perspectives in this field will also be discussed.

Keywords: Cancer therapy; Prognosis; Stanniocalcin 2; Stress Response; Tumorigenesis; Tumour progression.

Fig. 1

The comparaison of STC2 protein sequences among indicated species. It suggests highly phylogenetic consevation in different vertebrates

Fig. 2

The mRNA expression of STC2 in human normal tissues. The panels A & B were generated using online tool: The Protein Atlas (https://www.proteinatlas.org/)

Fig. 3

The comparison of STC2 expression between human tumours and their relative normal counterparts using the online tool (http://gepia2.cancer-pku.cn/). Panel A: CHOL, cholangiocarcinoma; COAD, colon adenocarcinoma; ESCA, esophageal carcinoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous cell carcinoma; KIRC, kidney renal clear cell carcinoma; LGG, brain lower grade glioma; OV, ovarian serous cystadenocarcinoma; READ, rectum adenocarcinoma; UCEC, uterine corpus endometrial carcinoma; UCS, uterine carcinosarcoma. Panel B: LAML, acute Myeloid Leukemia; SKCM, skin cutaneous melanoma. Panel C: ACC, Adrenocortical carcinoma; CESC, Cervical squamous cell carcinoma and endocervical adenocarcinoma; DLBC, Lymphoid Neoplasm Diffuse Large B-cell Lymphoma; KICH, Kidney Chromophobe; LIHC, Liver hepatocellular carcinoma; LUSC, Lung squamous cell carcinoma; PCPG, Pheochromocytoma and Paraganglioma; SARC, Sarcoma; STAD, Stomach adenocarcinoma; TGCT, Testicular Germ Cell Tumours; THYM, Thymoma. Panel D: BLCA, Bladder Urothelial Carcinoma; BRCA, Breast invasive carcinoma; KIRP, Kidney renal papillary cell carcinoma; LUAD, Lung adenocarcinoma; PAAD, Pancreatic adenocarcinoma; PRAD, Prostate adenocarcinoma; THCA, Thyroid carcinoma. Red bar: tumour tissues; Gray bar: normal tissues. Red star indicates p values less than 0.05

Fig. 4

STC2 modulates the severity of ER stress response, promotes cell survival and prevents apoptosis. Hypoxia, nutrient depletion associated ATP depletion, and oxidative stress trigger ER stress. Similarly, therapeutic treatment and some compounds disrupting ER functions also trigger ER stress. Under such conditions, BiP, the negative regulator of ATF6, PERK and IRE1, is sequestrated by misfolded proteins accumulated in the ER lumen. The activation of ATF6 (tATF6, truncated and activated form), ATF4 and XBP1 leads to transcriptional upregulation of genes involved in ER homeostasis, ER biogenesis, inflammatory response, protein folding and degradation. Severe and prolonged ER stress leads to the activation of JNK/NF-κB and CHOP pathways which promote apoptosis. Under moderate stress conditions, the p-eIF2α-ATF4 axis serves as a modulator of the severity of ER stress response by activating three down stress genes: 1) as the negative regulator of ER stress, BiP upregulation facilitates restoring ER homeostasis; 2) GADD34, a phosphoprotein phosphatase, directly dephosphorylates eIF2α to attenuate ATF4-mediated stress response; and 3) importantly, STC2 performs its function through affecting ATF4 or calcineurin, a calcium and calmodulin dependent serine/threonine protein phosphatase that is evidenced by the report showing aluminium toxicity causes ER stress, which activates IRE1β, but not ATF4, finally leading to apoptosis

Fig. 5

The biological functions of STC2 under hypoxic conditions. STC2 promoter contains hypoxia response elements (HREs) and amino acid response elements (AAREs). Under hypoxic conditions, HIF-1α is stabilized, and forms the HIF-1 heterodimer through interacting with HIF-1β. Then, HIF-1 is translocated into the nucleus where it binds to CBP/p300 and form a transcription complex to induce the expression of STC2. In addition, hypoxia also induces the expression of ATF4 through increased gene transcription, protein translation and protein stabilization. Thereafter, ATF4 is translocated into nucleus and form a transcriptional complex with co-factors to enhance the expression of downstream genes; however, it remains elusive whether ATF4 also contributes to STC2 upregulation under hypoxic conditions. Functionally, STC2 promotes cell cycle progression through enhancing cyclin D expression and Rb phosphorylation; STC2 induces epithelial-mesenchymal transition (EMT) through upregulating mesenchymal markers (N-cadherin and vimentin) and downregulating E-cadherin; in addition, STC2 can drive cell migration and invasion through the upregulation of matrix metalloproteinase (MMP) -2 and -9