BMB Reports 2022; 55(2): 72-80
Odorant receptors in cancer
Chan Chung1,2,#,* , Hee Jin Cho3,4,# , ChaeEun Lee1,2 & JaeHyung Koo1,2,5,*
1Department of New Biology, DGIST, Daegu 42988, 2New Biology Research Center (NBRC), DGIST, Daegu 42988, 3Department of Biomedical Convergence Science and Technology, Kyungpook National University, Daegu 41566, 4Cell and Matrix Research Institute, Kyungpook National University, Daegu 41944, 5Korea Brain Research Institute (KBRI), Daegu 41062, Korea
Correspondence to: Chan Chung, Tel: +82-53-785-1660; Fax: +82-53-785-1819; E-mail:; JaeHyung Koo, Tel: +82-53-785-6112; Fax: +82-53-785-1819; E-mail:
#These authors contributed equally to this work.
Received: January 10, 2022; Revised: January 20, 2022; Accepted: January 20, 2022; Published online: February 28, 2022.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Odorant receptors (ORs), the largest subfamily of G proteincoupled receptors, detect odorants in the nose. In addition, ORs were recently shown to be expressed in many nonolfactory tissues and cells, indicating that these receptors have physiological and pathophysiological roles beyond olfaction. Many ORs are expressed by tumor cells and tissues, suggesting that they may be associated with cancer progression or may be cancer biomarkers. This review describes OR expression in various types of cancer and the association of these receptors with various types of signaling mechanisms. In addition, the clinical relevance and significance of the levels of OR expression were evaluated. Namely, levels of OR expression in cancer were analyzed based on RNA-sequencing data reported in the Cancer Genome Atlas; OR expression patterns were visualized using t-distributed stochastic neighbor embedding (t-SNE); and the associations between patient survival and levels of OR expression were analyzed. These analyses of the relationships between patient survival and expression patterns obtained from an open mRNA database in cancer patients indicate that ORs may be cancer biomarkers and therapeutic targets.
Keywords: Cancer, Ectopic expression, Odorant receptor (OR), TCGA, t-SNE

Odorant receptors (ORs) are G protein-coupled receptors (GPCRs) that are essential for detecting and distinguishing among odorants. ORs were originally detected by analyses of the extent of receptor diversity and their expression pattern in the olfactory system (1). Since the first ORs were discovered in rats, approximately 400 of more than 800 human GPCRs and 1,000 of an estimated 1,700 mouse GPCRs have been identified (2, 3). Because of their intrinsic function, ORs were originally thought to be expressed only in olfactory epithelium, but they were later detected in dog ovaries and testes, including in germ cells (4). To date, ORs have been found to be expressed in various tissues and cells (5-8), including the bladder, thyroid, and thymus (9); the kidneys (10), skin (11), pancreas (12), liver (13), and brain (14-16); and cancer cells (6, 17, 18). This widespread expression of ORs in nonolfactory tissues and cells suggests that ORs are involved in various biological functions beyond sense of smell (5, 6).

Studies have shown that ORs are expressed in tumor cells and tissues, including hepatocarcinoma cells (19), breast carcinoma tissues (20), prostate cancer cells (21), enterochromaffin tumor cells (22), melanomas (23), and urinary bladder cancers (24). Functional evaluations have shown that ORs in these cancers regulate cancer cell invasiveness, metastasis, differentiation, and prognosis (25, 26), as well as being involved in cell signaling, proliferation, and apoptosis (5-7). This review describes current knowledge about the expression of distinct ORs in cancers, as well as the canonical and non-canonical signaling pathways induced by these ORs. In addition, OR expression pattern in various cancers were analyzed based on RNA-sequencing data reported in the Cancer Genome Atlas (TCGA), and the associations between patient survival outcomes and OR levels were analyzed to determine the clinical relevance and significances of OR expression in tumors.


Prostate cancer

The level of expression of OR51E2, also called PSGR and prostate-specific GPCR, was high in prostate cancer (21, 22, 27-32). The level of OR51E2 mRNA was found to be significantly higher in prostate tissue samples from patients with prostate intraepithelial neoplasia and prostate cancer than in normal prostate tissues and tissues from patients with benign prostatic hyperplasia (33). These results suggest that OR51E2 may play an important role in the development of early prostate cancer (26). In addition, the level of OR51E1 mRNA, also called PSGR2 and the paralogue of OR51E2, was higher in tissue samples of patients with high grade prostate intraepithelial neoplasia and prostate cancers (30, 34, 35). Although both ORs were thought to be useful and specific biomarkers for early prostate cancer, their expression patterns were found to be distinct at the cellular level and varied within tumor samples. Both ORs were detected in basal gland structures and were diffusely expressed throughout the cytoplasm of prostate epithelial cells. However, OR51E1 was mainly expressed in apical luminal cell structures, indicating a membrane localization pattern. OR51E1 protein was highly expressed in most lymph nodes and distant metastases of prostate cancers, indi-cating that OR51E1 may have a distinct physiological function in advanced prostate cancers (36). Also, OR1D2 mRNA is highly expressed in LNCaP prostate carcinoma cells (37). In our analysis, the expression of ORs was re-evaluated in cancer patients by cancer types by t-distributed stochastic neighbor embedding (t-SNE) clustering of OR genes using RNA-sequencing data from the TCGA database. These t-SNE analyses showed that OR expression patterns differed among types of cancer (Fig. 1A) and between tumor and normal tissue samples of the same tissue types (Fig. 1B). Detailed analysis of the expression of each OR gene across various cancer types (Fig. 1C-O) showed that the levels of OR51E1 and OR51E2 were also highest in prostate adenocarcinomas (PRAD), consistent with previous study showing that OR51E1, OR51E2, and OR1D2 expression were found in PRAD. Interestingly, they were expressed in many other types of cancers, such as kidney renal clear cell carcinoma (KIRC) and glioblastoma multiforme (GBM) (Fig. 1C, D). By contrast, the level of OR1D2 expression in PRAD was not noticeable in our t-SNE analysis (data not shown).

Breast cancer

Analysis of samples stored in the sequence read archive, the RNA-sequencing database (, showed that OR2B6 was expressed in 73% of breast carcinoma cell lines and in over 80% of primary breast carcinoma tissues, but not in normal breast tissue, suggesting that OR2B6 may be a reliable marker for breast cancer (20, 38). An analysis of OR transcript abundance in patients with invasive breast carcinoma found that OR2W3, OR2T8, and OR2B6 mRNAs correlated with breast cancer progression (20, 39). In addition, OR2T6 was shown to be overexpressed in breast cancer tissue and to tightly correlate with lymph node metastasis as well as with higher tumor/node/metastasis staging. Patients with OR2T6-positive breast cancer had a poor prognosis, as shown by reduced overall survival (OS) and disease-free survival (DFS) (40). Although our analysis of the TCGA database also found that OR2B6, OR2W3, and OR2T8 were expressed in breast invasive carcinoma (BRCA) samples, these ORs were also expressed in other types of cancer, including PRAD, GBM, lower grade glioma (LGG), and acute myeloid leukemia (LAML) (Fig. 1E-G). Previous studies and our analysis show that high levels of OR51E2 expression were also associated with poor prognosis in breast cancer patients (Fig. 2A) (25).


OR51E2 has been reported to influence melanocyte homeostasis, with activation of OR51E2 enhancing melanogenesis and dendritogenesis and reducing melanocyte proliferation, results indicating that OR51E2 regulates melanocyte differentiation (41). In addition, OR51E2 mRNA and protein levels were found to be upregulated in melanoma tissue sections and primary cells from melanoma tissues, and OR51E2 activation by β-ionone was shown to inhibit the proliferation and migration of pri-mary melanoma cells (23). However, OR51E2 expression was relatively low in skin cutaneous melanoma (SKCM) samples in the TCGA database compared with other cancer types (Fig. 1D). By contrast, t-SNE visualization showed that OR7A5 and OR2C3 were highly expressed in SKCM (Fig. 1H, I).

Colon cancer

OR51B4 was found to be highly expressed in HCT116 colon cancer cells. Troenan, its specific ligand, was shown to activate OR51B4, inducing the activation of phospholipase C (PLC) via Ca2+ influx. PLC was found to be involved in the increased phosphorylation of p38 and the decreased phosphorylation of Akt in colon cancer cells. This signal transduction led to the inhibition of cell proliferation and migration (42). OR7C1 may be another potential biomarker in colon cancer. OR7C1-positive patients showed higher tumorigenicity than OR7C1-negative patients (43). By contrast, our analysis showed that OR51B4 and OR7C1 expression was not detectable in colon adenocarcinoma (COAD) (data not shown), whereas OR51E1 was expressed in COAD (Fig. 1C).

Bladder cancer

OR10H1 mRNA and protein levels were found to be significantly higher in cancerous bladder tissue than in normal bladder (24). Our analysis of TCGA data also found that the OR10H1 was highly expressed in bladder urothelial carcinoma (BLCA) (Fig. 1J), suggesting that OR10H1 may be a potential biomarker for bladder cancer. To functionally characterize OR10H1, it was activated by the sandalwood-related compound, sandranol, in BFTC905 bladder cancer cells. Sandranol altered cell morphology; reduced cell viability, proliferation, and migration; and enhanced apoptosis (24). In addition, OR7A5 was found to be expressed in a subset of BLCA patients, with high OR7A5 expression associated with poor prognosis in patients with BLCA (Fig. 1H and 2B).

Neuroendocrine carcinomas

OR51E1 was identified from microarray analysis and from expressed sequence tag database analysis by comparisons of normal and tumor tissues. OR51E1 level was found to be higher in laser-captured small intestine neuroendocrine carcinomas than in cells from the adjacent microenvironment (44, 45).

Liver cancer

OR1A1 was found to be overexpressed in plasma membranes of hepatocarcinoma cells. OR1A1 activated by the ligand (−)-carvone induced the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response element-binding (CREB) signaling pathway without altering the intracellular Ca2+ concentration. Activated OR1A1 reduced intracellular concentrations of triglycerides, but not of cholesterol (46). In addition, OR1A2, a paralogue of OR1A1, and OR8B3 were found to be expressed in a monoterpene-activated hepatocellular carcinoma (HCC) cell line. Activation of OR1A2 resulted not only in an increase in cytosolic Ca2+ level through the activation of a cAMP-dependent signaling pathway, but also induced the phosphorylation of p38-mitogen-activated protein kinase (MAPK) and a reduction in cell proliferation, showing that ORs affect HCC progression (19). However, analysis of patient data revealed that OR1A1 and OR1A2 were only slightly expressed in cancers including liver hepatocellular carcinoma (LIHC) (data not shown). We found that high OR7A5 expression in patients with HCC was associated with poor prognosis (Fig. 2C).

Lung cancer

OR2J3 was found to be expressed in cell membranes of the helional-activated non-small-cell lung cancer (NSCLC) cell line A549, increasing intracellular Ca2+ concentration. Activation of OR2J3 led to the phosphorylation of ERK and components of the ERK signaling pathway, including ERK1/2, RSK1/2/3, MEK1/2, and c-Raf. Helional-induced OR2J3 inhibited cell migration and decreased cell proliferation (47). Despite OR2J3 expression being confirmed in this NSCLC cell line, its expression levels in patients, as shown in the TCGA database, were negligible (data not shown). OR51E1 was found to be highly expressed in the lung carcinoid cell lines NCI-H727 and NCI-H720 and in frozen lung tumor specimens (48), consistent with previous results (Fig. 1C and 2D). Compared with xenografts of LLC murine Lewis lung carcinoma cell on wild-type mice, xenografts of these cells on mice with knockout of Olfr78, a mouse analog of OR51E2, showed reduced tumor growth and metastasis. In addition, TCGA analysis showed that lower OR51E2 expression correlated significantly with better survival (25). Solid-phase microextraction GC/MS identified a cancer-specific odorant, 2-ethyl-1-hexanol, in the SK-MES cancer cell line, and screening of human ORs found that OR4D11P was a sensitive and selective receptor of 2-ethyl-1-hexanol (49).

Brain cancer (Glioma)

Although ORs particular to glioma have not been identified, we recently suggested that several ORs (18), which had not been mentioned in a report on the importance of GPCR in glioma (50), were clinically relevant and significant in glioma. Evaluations of patient-derived specimens and primary cell cultures have identified several ORs associated with glioma. One study evaluating the transcriptional regulatory networks of mesenchymal-associated tumor-associated macrophages in glioblastoma identified 21 candidate transcriptional master regulators, including peroxisome proliferator-activated receptor gamma (PPAR-γ) and nuclear factor-kappa B (NF-κB). Interestingly, OR4N2 and OR7A5 were found to be involved in the transcriptional regulatory network (51), and OR51E2 was involved in glio-blastoma progression. Analysis of glioblastoma patients in the TCGA database showed that high expression of OR51E2 was associated with poor prognosis (25). In addition, a four-gene signature (ASPM, CCNB1, EXO1, and KIF23) in patients with LGG correlated negatively with response to treatment with temozolomide (TMZ), which is frequently used as primary chemotherapy for LGG. A comparison of expression levels and DNA methylation profiles suggested that OR51F2 may act as a potential downstream effector in glioblastoma (52). Our t-SNE analysis showed that OR expression profiles in gliomas were distinct from those in other types of solid tumors. These analyses confirmed that OR4N2, OR2L13, and OR4K1 were expressed in gliomas (Fig. 1K-M), along with OR51E1, OR51E2, OR2B6, OR7A5, OR10Q1 (Fig. 1C-E, H, N), and OR2W3 (Fig. 1F). In addition, the differential expression of several other OR genes, including OR51E1, OR51E2, OR4N2, OR4K1, OR7A5, OR7D2, and OR10AD1, in GBM and LGG suggested that these ORs were associated with prognosis in patients with glioma (Fig. 1A, 2E-K, and (18).


Canonical pathway

The canonical signal transduction of ORs involves the heterotrimeric G-protein, Golf. ORs are initially activated by binding to specific odorant(s). The alpha subunit of Golf (Gaolf) facilitates an exchange of GDP with GTP. GTP-bound Gaolf dissociates Gbg-heterodimer and binds to adenylyl cyclase III. This complex converts ATP to cAMP. Increased cAMP activates cyclic nucleotide-gated channels, which cause Ca2+ ion influx, leading to the generation of an action potential in the olfactory neuron axon (5, 6).

Non-canonical pathway

Unlike the classical pathway, ectopic ORs induce the non-canonical pathway in cancers. OR51E2 induces PI3 kinase-γ, leading to cell invasion and metastasis (22). OR51E2 also activates NF-κB via the phosphatidylinositol-3-kinase/Akt pathway, inducing chronic inflammation (26). We recently reported that lactate-activated Olfr78/OR51E2 induces the differentiation of bone marrow-derived macrophages into M2-tumor-associated macrophages. Depletion of Olfr78 reduces tumor progression and metastasis and increases antitumor immunity (25). OR51B5, which is activated by isononyl alcohol, increases intracellular Ca2+ levels in blood cells derived from a patient with acute myeloid leukemia (LAML) and in a human erythroleukemic cell line K562. Activated OR51B5 reduces p38-MAPK phosphorylation, reducing cell proliferation (53). Lyral-activated OR10J5 increases Ca2+ levels and the phosphorylation of AKT and ERK in human aorta, coronary artery, and umbilical vein endothelial cells (HUVEC). Lyral also induces the migration of HUVECs via OR10J5 and enhances angiogenesis in vivo (54). Following activation with (−)-citronellal, OR1A2 induces MAPK signaling, but not ERK1/2 and SAPK/JNK signaling, and reduces the proliferation of hepatocarcinoma cells (19). Not all pathways accompany the increase in cytosolic Ca2+ level at initial activation. For example, activation of OR1A1 by its ligand (−)-carvone increases cAMP, a step in the canonical pathway, but not intracellular Ca2+, leading to PKA activation. PKA upregulates CREB-responsive genes, including hairy and enhancer of split (HES)-1 and PPAR-γ by phosphorylating CREB in hepatocytes (46). Analysis of single-cell transcriptomes in cancer cells revealed a complicated signaling network in response to OR expression. A metascape analysis of BRCA-associated ORs showed that prominent biological functions included regulation of the cell cycle, transcriptional or translational regulation, PTEN regulation, metabolic processes, and DNA repair (17). This approach confirmed previous findings of signal transduction by ORs, and suggested new and previously unknown pathways in OR-related cancers.


ORs are expressed in many nonolfactory tissues and cells (5, 6), although the levels of certain ORs in normal tissue are extremely low or undetectable. Many of these ORs, however, are detected during early stages of cancer, suggesting that ORs may be potential biomarkers for cancer and the need to identify target ORs in specific cancer types. Most studies of ORs in cancer have involved cancer cell lines, with few studies assessing OR expression in tissues derived from cancer patients. In particular, the functions of ORs in cancers have been generally assessed by treating cell lines with known OR ligands and detecting changes in intracellular Ca2+ or signaling mechanisms (Table 1). However, findings in cell lines may not reflect tumor processes in cancer patients, especially if stimulation of cell lines by known ligands does not involve the expected pathway. Table 1 summarizes in vitro results of cancer-related ORs, as well as their possible associations with results in patients, as determined by OR expression in RNA-seq samples of cancers in the TCGA database and visualization of expression patterns by t-SNE (Fig. 1A). These t-SNE analyses showed that OR expression profiles differed in tumor and matched normal tissue samples (Fig. 1B), indicating that tumor tissues show both tumor-specific and tissue-specific OR expression. Interestingly, OR51E1 and OR51E2, which were identified in prostate cancer, were also expressed in KIRC (Fig. 1C, D), consistent with reports showing that OR51E2/Olfr78 is expressed in the kidneys and is involved in the regulation of blood pressure (10). Moreover, OR51E1 was more highly expressed in GBM than in LGG, consistent with our recent findings (18). By contrast, OR4N2 and OR2L13 were expressed in LGG but not GBM, with t-SNE analysis confirming our previous findings (Fig. 1K, L). In addition to OR51E1/2, OR4N2, and OR2L13, we evaluated the levels of expression of additional OR genes described in Table 1 as well (Fig. 1E-J, M, N). Several of these OR genes were found to be tumor- and/or tissue-specific. For example, OR2A4 was expressed only in KIRC, suggesting that OR2A4 may be a potential therapeutic target or biomarker of KIRC (Fig. 1O). Kaplan-Meier survival analysis comparing survival in patients with low and high levels of each OR in Table 1 identified ORs that differed significantly (Fig. 2). For example, high expression of OR51E2 was associated with poor prognosis in patients with breast cancer and glioma, and high expression of OR7A5 was a risk factor for poorer outcomes in patients with liver, bladder, and kidney cancer and LGG. By contrast, high levels of OR4N2, OR7D2, and OR4K1 expression were associated with longer OS in patients with LGG.

Although the main function of ORs is sensing odorants in olfactory epithelium, ORs can also regulate cancer cell proliferation, apoptosis, migration, invasion, and senescence. However, the signaling pathways by which ORs act in cancers remain poorly understood. Several ORs have been shown to activate PKA and MAPK (21, 40, 53), and analysis of single-cell transcriptomes in cancer revealed that OR expression was associated with a complicated signaling network. Metascape analysis showed that breast cancer-associated ORs were involved in the cell cycle, transcriptional or translation regulation, metabolic processes, and DNA repair (17). Additional research on the mechanism of action of ORs in cancer may lead to the development of OR-targeting drugs.


This work was supported by grants from the National Research Foundation (2021R1A2C1009258 to J. Koo and 2021R1C1C1004653 to H.J. Cho), the Bio & Medical Technology Development Program (2020M3A9D3038435 to J. Koo), the Korean Mouse Phenotype Center (2019M3A9D5A01102797 to J. Koo), and the DGIST Start-up Fund Program of the Ministry of Science and ICT (2021050001 to C. Chung).


The authors have no conflicting interests.

Fig. 1. Relationships between distinct human OR expression profiles and tumor types. (A-O) t-Stochastic nearest neighbor (t-SNE, perplexity = 50) plots of TCGA RNA-seq samples (tumor N = 5523, normal N = 471) for 842 OR genes, colored by tumor types (A), sample types (B), or the expression of OR genes (C-O). The color scale indicates Z-normalized log2(transcripts per million (TPM)+1) values of each gene (C-O). The range of color scale is from -2 (gray) to 2 (red). BLCA, bladder urothelial carcinoma; BRCA, breast invasive carcinoma; COAD, colon adenocarcinoma; GBM, glioblastoma multiforme; KIRC, kidney renal clear cell carcinoma; LAML, acute myeloid leukemia; LGG, lower grade glioma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; PRAD, prostate adeno-carcinoma; READ, rectum adenocarcinoma; SKCM, skin cutaneous melanoma. The mouse ortholog of each human OR is in parentheses.
Fig. 2. Kaplan-Meier analysis of overall survival in patients with high and low levels of expression of human ORs. OR51E2 in BRCA (A), OR7A5 in BLCA (B), OR7A5 in LIHC (C), OR51E1 in LUAD (D), OR51E1 in all gliomas (E), OR51E2 in all gliomas (F), OR4N2 in all gliomas (G), OR4K1 in all gliomas (H), OR7A5 in LGG (I), OR7D2 in all gliomas (J), OR10AD1 in all gliomas (K), and OR7A5 in KIRC (L). BRCA, breast invasive carcinoma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; BLCA, bladder urothelial carcinoma; LGG, lower grade glioma; GBM, glioblastoma multiforme; KIRC, kidney renal clear cell carcinoma. The mouse ortholog of each human OR is in parentheses.

Expression of odorant receptors in various human tumor types

Cancer type Odorant receptor Ligands/sample origin Function Ref
Prostate cancer OR51E1 (PSGR2) Nonanoic acid, medium-chain fatty acids Senescence, growth suppression, cytostatic effects, cell death (21, 30, 34-36, 55, 56)
Fig. 1C
OR51E2 (PSGR) β-Ionone, acetate, propionate Activation of the MAPK family and inhibition of cell proliferation (21, 22, 26-33, 55, 57, 58)
Fig. 1D


Uptake of both bourgeonal conjugates in vitro and in vivo (37)
Breast cancer OR2B6 Unknown/patient specimens Breast cancer proliferation and invasion (17, 20, 38, 39)
Fig. 1E
OR6M1 Anthraquinone, rutin AQ induced the death of MCF-7 cells, which was inhibited by rutin (59)
OR2W3 Unknown/patient specimens Breast cancer proliferation and invasion (20, 39)
Fig. 1F
OR2T8 Unknown/patient specimens Breast cancer proliferation and invasion (39)
Fig. 1G
OR2T6 Unknown/patient specimens Increase in cell proliferation, invasion, and migration via EMT-MAPK signaling (40)
OR51E2 TCGA database Poor prognosis (25)
Fig. 2A
OR4F17 scRNA-seq Metastasis (negative correlation) (17)
scRNA-Seq (17)
Melanoma OR51E2 β-Ionone Inhibition of cell proliferation and migration (23, 41)
OR2C3 TCGA database (60)
Fig. 1I
OR1A1 scRNA-Seq Skin cutaneous melanoma (17)
Colon cancer OR51B4 Troenan Apoptosis and inhibition of proliferation and migration (42)
OR7C1 Patient specimens Correlation with tumorigenicity (43)
Bladder cancer OR10H1 Santalol and Sandranol Decreased cell viability, proliferation and migration; increased apoptosis (24)
Fig. 1J
Neuroendocrine carcinomas OR51E1 Tumor tissue Increased expression (44, 45)
Liver cancer OR1A1 (−)-Carvone Regulation of hepatic triglyceride metabolism (46)
OR1A2 Monoterpene (−)-citronellal Decreased cell proliferation (19)
OR8B3 Monoterpene (−)-citronellal No changes in intracellular Ca2+ levels in response to carvone, the activating ligand (19)
Lung cancer OR2J3 Helional Inhibition of cell migration and decreased proliferation via the ERK pathway (47)
OR51E1 Patient specimens High expression in lung carcinoids (48)
OR51E2 TCGA database Poor prognosis (25)
OR4D11P 2-Ethyl-1-hexanol Potential lung cancer biomarker (49)
scRNA-Seq Invasion (negative correlation) (17)
Brain cancer (Glioma)
OR4N2 Patient specimens and primary cell culture MA-TAM target gene (18, 51),
Fig. 1K
Fig. 2G
OR7D2 scRNA-Seq Astrocytoma (17)
Fig. 2J
OR4F17 scRNA-Seq Glioblastoma (17)
OR7A5 Patient specimens and primary cell culture MA-TAM target gene (51)
Fig. 1H
Fig. 2I
OR51E2 TCGA database Poor prognosis (18, 25)
Fig. 2F
OR51F2 TCGA database treated with TMZ Efficacy of TMZ therapy (52)
OR4Q3 TCGA database (61)
OR7E156P TCGA database (62)
COSMIC database Astrocytoma (63), Fig. 1N
Fig. 1M, Fig. 2H
OR2M3 scRNA-Seq Renal cell carcinoma (17)
Blood OR10H1 scRNA-Seq Chronic myeloid leukemia (17)
OR2AT4 Sandalore, antagonist Phenirat/acute myeloid leukemia (AML) patientshuman chronic myelogenous leukemia (CML) cell line Reduced proliferation and induced apoptosis (64)
OR51B5 Isononyl alcohol/AML, CML Reduced proliferation (53)

COSMIC: catalogue of somatic mutations in cancer database, TCGA: the cancer genome atlas database.

  1. Buck L and Axel R (1991) A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell 65, 175-187
    Pubmed CrossRef
  2. Niimura Y (2009) Evolutionary dynamics of olfactory receptor genes in chordates: interaction between environments and genomic contents. Hum Genomics 4, 107-118
    Pubmed KoreaMed CrossRef
  3. Kroeze WK, Sheffler DJ and Roth BL (2003) G-protein-coupled receptors at a glance. J Cell Sci 116, 4867-4869
    Pubmed CrossRef
  4. Parmentier M, Libert F, Schurmans S et al (1992) Expression of members of the putative olfactory receptor gene family in mammalian germ cells. Nature 355, 453-455
    Pubmed CrossRef
  5. Kang N and Koo J (2012) Olfactory receptors in non-chemosensory tissues. BMB Rep 45, 612-622
    Pubmed KoreaMed CrossRef
  6. Massberg D and Hatt H (2018) Human olfactory receptors: novel cellular functions outside of the nose. Physiol Rev 98, 1739-1763
    Pubmed CrossRef
  7. Di Pizio A, Behrens M and Krautwurst D (2019) Beyond the flavour: the potential druggability of chemosensory G protein-coupled receptors. Int J Mol Sci 20, 1402
    Pubmed KoreaMed CrossRef
  8. Ferrer I, Garcia-Esparcia P, Carmona M et al (2016) Olfactory receptors in non-chemosensory organs: the nervous system in health and disease. Front Aging Neurosci 8, 163
    Pubmed KoreaMed CrossRef
  9. Kang N, Kim H, Jae Y et al (2015) Olfactory marker protein expression is an indicator of olfactory receptor-associated events in non-olfactory tissues. PLoS One 10, e0116097
    Pubmed KoreaMed CrossRef
  10. Pluznick JL, Protzko RJ, Gevorgyan H et al (2013) Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation. Proc Natl Acad Sci U S A 110, 4410-4415
    Pubmed KoreaMed CrossRef
  11. Busse D, Kudella P, Grüning NM et al (2014) A synthetic sandalwood odorant induces wound-healing processes in human keratinocytes via the olfactory receptor OR2AT4. J Invest Dermatol 134, 2823-2832
    Pubmed CrossRef
  12. Kang N, Bahk YY, Lee N et al (2015) Olfactory receptor Olfr544 responding to azelaic acid regulates glucagon secretion in alpha-cells of mouse pancreatic islets. Biochem Biophys Res Commun 460, 616-621
    Pubmed CrossRef
  13. Wu C, Hwang SH, Jia Y et al (2017) Olfactory receptor 544 reduces adiposity by steering fuel preference toward fats. J Clin Invest 127, 4118-4123
    Pubmed KoreaMed CrossRef
  14. Garcia-Esparcia P, Schluter A, Carmona M et al (2013) Functional genomics reveals dysregulation of cortical olfactory receptors in Parkinson disease: novel putative chemoreceptors in the human brain. J Neuropathol Exp Neurol 72, 524-539
    Pubmed CrossRef
  15. Lee N, Jae Y, Kim M et al (2020) A pathogen-derived metabolite induces microglial activation via odorant receptors. FEBS J 287, 3841-3870
    Pubmed CrossRef
  16. Cho T, Lee C, Lee N, Hong YR and Koo J (2019) Small-chain fatty acid activates astrocytic odorant receptor Olfr920. Biochem Biophys Res Commun 510, 383-387
    Pubmed CrossRef
  17. Kalra S, Mittal A, Gupta K et al (2020) Analysis of single-cell transcriptomes links enrichment of olfactory receptors with cancer cell differentiation status and prognosis. Commun Biol 3, 506
    Pubmed KoreaMed CrossRef
  18. Cho HJ and Koo J (2021) Odorant G protein-coupled receptors as potential therapeutic targets for adult diffuse gliomas: a systematic analysis and review. BMB Rep 54, 601-607
    Pubmed KoreaMed CrossRef
  19. Massberg D, Simon A, Haussinger D et al (2015) Monoterpene (−)-citronellal affects hepatocarcinoma cell signaling via an olfactory receptor. Arch Biochem Biophys 566, 100-109
    Pubmed CrossRef
  20. Weber L, Massberg D, Becker C et al (2018) Olfactory receptors as biomarkers in human breast carcinoma tissues. Front Oncol 8, 33
    Pubmed KoreaMed CrossRef
  21. Neuhaus EM, Zhang W, Gelis L, Deng Y, Noldus J and Hatt H (2009) Activation of an olfactory receptor inhibits proliferation of prostate cancer cells. J Biol Chem 284, 16218-16225
    Pubmed KoreaMed CrossRef
  22. Sanz G, Leray I, Dewaele A et al (2014) Promotion of cancer cell invasiveness and metastasis emergence caused by olfactory receptor stimulation. PLoS One 9, e85110
    Pubmed KoreaMed CrossRef
  23. Gelis L, Jovancevic N, Bechara FG, Neuhaus EM and Hatt H (2017) Functional expression of olfactory receptors in human primary melanoma and melanoma metastasis. Exp Dermatol 26, 569-576
    Pubmed CrossRef
  24. Weber L, Schulz WA, Philippou S et al (2018) Characterization of the olfactory receptor OR10H1 in human urinary bladder cancer. Front Physiol 9, 456
    Pubmed KoreaMed CrossRef
  25. Vadevoo SMP, Gunassekaran GR, Lee C et al (2021) The macrophage odorant receptor Olfr78 mediates the lactate-induced M2 phenotype of tumor-associated macrophages. Proc Natl Acad Sci U S A 118, e210234118
    Pubmed CrossRef
  26. Rodriguez M, Luo W, Weng J et al (2014) PSGR promotes prostatic intraepithelial neoplasia and prostate cancer xenograft growth through NF-kappaB. Oncogenesis 3, e114
    Pubmed KoreaMed CrossRef
  27. Xu LL, Stackhouse BG, Florence K et al (2000) PSGR, a novel prostate-specific gene with homology to a G protein-coupled receptor, is overexpressed in prostate cancer. Cancer Res 60, 6568-6572
  28. Xu LL, Sun C, Petrovics G et al (2006) Quantitative expression profile of PSGR in prostate cancer. Prostate Cancer Prostatic Dis 9, 56-61
    Pubmed CrossRef
  29. Cao W, Li F, Yao J and Yu J (2015) Prostate specific G protein coupled receptor is associated with prostate cancer prognosis and affects cancer cell proliferation and invasion. BMC Cancer 15, 915
    Pubmed KoreaMed CrossRef
  30. Wang J, Weng J, Cai Y, Penland R, Liu M and Ittmann M (2006) The prostate-specific G-protein coupled receptors PSGR and PSGR2 are prostate cancer biomarkers that are complementary to alpha-methylacyl-CoA racemase. Prostate 66, 847-857
    Pubmed CrossRef
  31. Rigau M, Morote J, Mir MC et al (2010) PSGR and PCA3 as biomarkers for the detection of prostate cancer in urine. Prostate 70, 1760-1767
    Pubmed CrossRef
  32. Weng J, Ma W, Mitchell D, Zhang J and Liu M (2005) Regulation of human prostate-specific G-protein coupled receptor, PSGR, by two distinct promoters and growth factors. J Cell Biochem 96, 1034-1048
    Pubmed CrossRef
  33. Weng J, Wang J, Cai Y et al (2005) Increased expression of prostate-specific G-protein-coupled receptor in human prostate intraepithelial neoplasia and prostate cancers. Int J Cancer Res 113, 811-818
    Pubmed CrossRef
  34. Weigle B, Fuessel S, Ebner R et al (2004) D-GPCR: a novel putative G protein-coupled receptor overexpressed in prostate cancer and prostate. Biochem Biophys Res Commun 322, 239-249
    Pubmed CrossRef
  35. Fuessel S, Weigle B, Schmidt U et al (2006) Transcript quant-ification of Dresden G protein-coupled receptor (D-GPCR) in primary prostate cancer tissue pairs. Cancer Lett 236, 95-104
    Pubmed CrossRef
  36. Maßberg D, Jovancevic N, Offermann A et al (2016) The activation of OR51E1 causes growth suppression of human prostate cancer cells. Oncotarget 7, 48231-48249
    Pubmed KoreaMed CrossRef
  37. Sturzu A, Sheikh S, Echner H et al (2013) Novel bourgeonal fragrance conjugates for the detection of prostate cancer. Invest New Drugs 31, 1151-1157
    Pubmed CrossRef
  38. Muranen TA, Greco D, Fagerholm R et al (2011) Breast tumors from CHEK2 1100delC-mutation carriers: genomic landscape and clinical implications. Breast Cancer Res 13, R90
    Pubmed KoreaMed CrossRef
  39. Masjedi S, Zwiebel LJ and Giorgio TD (2019) Olfactory receptor gene abundance in invasive breast carcinoma. Sci Rep 9, 13736
    Pubmed KoreaMed CrossRef
  40. Li M, Wang X, Ma RR et al (2019) The olfactory receptor family 2, subfamily T, member 6 (OR2T6) is involved in breast cancer progression via initiating epithelial-mesenchymal transition and MAPK/ERK pathway. Front Oncol 9, 1210
    Pubmed KoreaMed CrossRef
  41. Gelis L, Jovancevic N, Veitinger S et al (2016) Functional characterization of the odorant receptor 51E2 in human melanocytes. J Biol Chem 291, 17772-17786
    Pubmed KoreaMed CrossRef
  42. Weber L, Al-Refae K, Ebbert J et al (2017) Activation of odorant receptor in colorectal cancer cells leads to inhibition of cell proliferation and apoptosis. PLoS One 12, e0172491
    Pubmed KoreaMed CrossRef
  43. Morita R, Hirohashi Y, Torigoe T et al (2016) Olfactory receptor family 7 subfamily C member 1 is a novel marker of colon cancer-initiating cells and is a potent target of immunotherapy. Clin Cancer Res 22, 3298-3309
    Pubmed CrossRef
  44. Leja J, Essaghir A, Essand M et al (2009) Novel markers for enterochromaffin cells and gastrointestinal neuroendocrine carcinomas. Mod Pathol 22, 261-272
    Pubmed CrossRef
  45. Cui T, Tsolakis AV, Li SC et al (2013) Olfactory receptor 51E1 protein as a potential novel tissue biomarker for small intestine neuroendocrine carcinomas. Eur J Endocrinol 168, 253-261
    Pubmed CrossRef
  46. Wu C, Jia Y, Lee JH et al (2015) Activation of OR1A1 suppresses PPAR-γ expression by inducing HES-1 in cultured hepatocytes. Int J Biochem Cell Biol 64, 75-80
    Pubmed CrossRef
  47. Kalbe B, Schulz VM, Schlimm M et al (2017) Helional-induced activation of human olfactory receptor 2J3 promotes apoptosis and inhibits proliferation in a non-small-cell lung cancer cell line. Eur J Cell Biol 96, 34-46
    Pubmed CrossRef
  48. Giandomenico V, Cui T, Grimelius L, ?berg K, Pelosi G and Tsolakis AV (2013) Olfactory receptor 51E1 as a novel target for diagnosis in somatostatin receptor-negative lung carcinoids. J Mol Endocrinol 51, 277-286
    Pubmed CrossRef
  49. Cho SW, Ko HJ and Park TH (2021) Identification of a lung cancer biomarker using a cancer cell line and screening of olfactory receptors for biomarker detection. Biotechnol Bioprocess Eng 26, 55-62
  50. Byrne KF, Pal A, Curtin JF, Stephens JC and Kinsella GK (2021) G-protein-coupled receptors as therapeutic targets for glioblastoma. Drug Discov Today 26, 2858-2870
    Pubmed CrossRef
  51. Sa JK, Chang N, Lee HW et al (2020) Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma. Genome Biol 21, 216
    Pubmed KoreaMed CrossRef
  52. Wang Q, He Z and Chen Y (2019) Comprehensive analysis reveals a 4-gene signature in predicting response to temozolomide in low-grade glioma patients. Cancer Control 26, 1073274819855118
    Pubmed KoreaMed CrossRef
  53. Manteniotis S, Wojcik S, Gothert JR et al (2016) Deorphanization and characterization of the ectopically expressed olfactory receptor OR51B5 in myelogenous leukemia cells. Cell Death Discov 2, 16010
    Pubmed KoreaMed CrossRef
  54. Kim SH, Yoon YC, Lee AS et al (2015) Expression of human olfactory receptor 10J5 in heart aorta, coronary artery, and endothelial cells and its functional role in angiogenesis. Biochem Biophys Res Commun 460, 404-408
    Pubmed CrossRef
  55. Pronin A and Slepak V (2021) Ectopically expressed olfactory receptors OR51E1 and OR51E2 suppress proliferation and promote cell death in a prostate cancer cell line. J Biol Chem 296, 100475
    Pubmed KoreaMed CrossRef
  56. Weng J, Wang J, Hu X, Wang F, Ittmann M and Liu M (2006) PSGR2, a novel G-protein coupled receptor, is overexpressed in human prostate cancer. Int J Cancer 118, 1471-1480
    Pubmed CrossRef
  57. Xia C, Ma W, Wang F, Hua S and Liu M (2001) Identification of a prostate-specific G-protein coupled receptor in prostate cancer. Oncogene 20, 5903-5907
    Pubmed CrossRef
  58. Cunha AC, Weigle B, Kiessling A, Bachmann M and Rieber EP (2006) Tissue-specificity of prostate specific antigens: comparative analysis of transcript levels in prostate and non-prostatic tissues. Cancer Lett 236, 229-238
    Pubmed CrossRef
  59. Choi YR, Shim J, Park JH, Kim YS and Kim MJ (2021) Discovery of orphan olfactory receptor 6M1 as a new anticancer target in MCF-7 cells by a combination of surface plasmon resonance-based and cell-based systems. Sensors (Basel) 21, 3468
    Pubmed KoreaMed CrossRef
  60. Ranzani M, Iyer V, Ibarra-Soria X et al (2017) Revisiting olfactory receptors as putative drivers of cancer. Wellcome Open Res 2, 9
    Pubmed KoreaMed CrossRef
  61. Yuan Y, Qi P, Xiang W, Yanhui L, Yu L and Qing M (2020) Multi-omics analysis reveals novel subtypes and driver genes in glioblastoma. Front Genet 11, 565341
    Pubmed KoreaMed CrossRef
  62. Zhao H, Du P, Peng R et al (2021) Long noncoding RNA OR7E156P/miR-143/HIF1A axis modulates the malignant behaviors of glioma cell and tumor growth in mice. Front Oncol 11, 690213
    Pubmed KoreaMed CrossRef
  63. Pappula AL, Rasheed S, Mirzaei G, Petreaca RC and Bouley RA (2021) A genome-wide profiling of glioma patients with an IDH1 mutation using the catalogue of somatic mutations in cancer database. Cancers (Basel) 13, 4299
    Pubmed KoreaMed CrossRef
  64. Manteniotis S, Wojcik S, Brauhoff P et al (2016) Functional characterization of the ectopically expressed olfactory receptor 2AT4 in human myelogenous leukemia. Cell Death Discov 2, 15070
    Pubmed KoreaMed CrossRef

This Article

Cited By Articles
  • CrossRef (0)

Author ORCID Information

Funding Information
  • National Research Foundation of Korea
      2021R1A2C1009258, 2021R1C1C1004653
  • Bio & Medical Technology Development Program
  • Korean Mouse Phenotype Center
  • Ministry of Science and ICT, South Korea


Social Network Service