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LIFR

Official Full Name
LIF receptor subunit alpha
Organism
Homo sapiens
GeneID
3977
Background
This gene encodes a protein that belongs to the type I cytokine receptor family. This protein combines with a high-affinity converter subunit, gp130, to form a receptor complex that mediates the action of the leukemia inhibitory factor, a polyfunctional cytokine that is involved in cellular differentiation, proliferation and survival in the adult and the embryo. Mutations in this gene cause Schwartz-Jampel syndrome type 2, a disease belonging to the group of the bent-bone dysplasias. A translocation that involves the promoter of this gene, t(5;8)(p13;q12) with the pleiomorphic adenoma gene 1, is associated with salivary gland pleiomorphic adenoma, a common type of benign epithelial tumor of the salivary gland. Multiple splice variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jun 2018]
Synonyms
SWS; SJS2; STWS; CD118; LIF-R;
Bio Chemical Class
Cytokine receptor
Protein Sequence
MMDIYVCLKRPSWMVDNKRMRTASNFQWLLSTFILLYLMNQVNSQKKGAPHDLKCVTNNLQVWNCSWKAPSGTGRGTDYEVCIENRSRSCYQLEKTSIKIPALSHGDYEITINSLHDFGSSTSKFTLNEQNVSLIPDTPEILNLSADFSTSTLYLKWNDRGSVFPHRSNVIWEIKVLRKESMELVKLVTHNTTLNGKDTLHHWSWASDMPLECAIHFVEIRCYIDNLHFSGLEEWSDWSPVKNISWIPDSQTKVFPQDKVILVGSDITFCCVSQEKVLSALIGHTNCPLIHLDGENVAIKIRNISVSASSGTNVVFTTEDNIFGTVIFAGYPPDTPQQLNCETHDLKEIICSWNPGRVTALVGPRATSYTLVESFSGKYVRLKRAEAPTNESYQLLFQMLPNQEIYNFTLNAHNPLGRSQSTILVNITEKVYPHTPTSFKVKDINSTAVKLSWHLPGNFAKINFLCEIEIKKSNSVQEQRNVTIKGVENSSYLVALDKLNPYTLYTFRIRCSTETFWKWSKWSNKKQHLTTEASPSKGPDTWREWSSDGKNLIIYWKPLPINEANGKILSYNVSCSSDEETQSLSEIPDPQHKAEIRLDKNDYIISVVAKNSVGSSPPSKIASMEIPNDDLKIEQVVGMGKGILLTWHYDPNMTCDYVIKWCNSSRSEPCLMDWRKVPSNSTETVIESDEFRPGIRYNFFLYGCRNQGYQLLRSMIGYIEELAPIVAPNFTVEDTSADSILVKWEDIPVEELRGFLRGYLFYFGKGERDTSKMRVLESGRSDIKVKNITDISQKTLRIADLQGKTSYHLVLRAYTDGGVGPEKSMYVVTKENSVGLIIAILIPVAVAVIVGVVTSILCYRKREWIKETFYPDIPNPENCKALQFQKSVCEGSSALKTLEMNPCTPNNVEVLETRSAFPKIEDTEIISPVAERPEDRSDAEPENHVVVSYCPPIIEEEIPNPAADEAGGTAQVIYIDVQSMYQPQAKPEEEQENDPVGGAGYKPQMHLPINSTVEDIAAEEDLDKTAGYRPQANVNTWNLVSPDSPRSIDSNSEIVSFGSPCSINSRQFLIPPKDEDSPKSNGGGWSFTNFFQNKPND
Open
Disease
Male infertility
Approved Drug
0
Clinical Trial Drug
1 +
Discontinued Drug
0

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Detailed Information

Leukemia inhibitory factor (LIF) is the most pleiotropic interleukin-6 (IL-6) cytokine family member. It transmits its biological signals through a membrane receptor complex composed of LIF receptor (LIFR) and the glycoprotein 130 (gp130). LIF first binds to LIFR, which then recruits gp130 to form a high-affinity receptor complex. Although LIFR lacks intrinsic tyrosine kinase activity, it constitutively associates with Janus kinases (JAKs) and the tyrosine kinase Tyk, thereby facilitating the activation of downstream signaling pathways.

LIF/LIFR-JAK-STAT3 signaling is upregulated in various tumors through autocrine and paracrine mechanisms, enhancing tumor cell proliferation and survival. LIF promotes mTORC1/p70S6K pathway activation, which accelerates tumor growth and suppresses DNA damage responses. In breast cancer, LIF/LIFR signaling facilitates tumor progression and metastasis via AKT-mTOR activation, while also promoting angiogenesis through the ERK/IL-8 axis. Additionally, it suppresses the tumor suppressor p53 through the STAT3/ID1/MDM2 signaling cascade.

Notably, LIFR is a common receptor for several cytokines including Oncostatin M (OSM), Ciliary Neurotrophic Factor (CNTF), and Cardiotrophin-1 (CTF1). These ligands share overlapping binding sites in the immunoglobulin-like domain of LIFR, although they exhibit different affinities and functional outcomes. The complexity of LIFR signaling is attributed to this ligand redundancy and differential downstream effects.

Figure 1: LIF/LIFR signaling diagram showing tumor-promoting effects via STAT3, mTOR, AKT, MAPK and tumor microenvironment regulation.Figure 1. Schematic representation of the oncogenic LIF/LIFR signaling pathway. (Viswanadhapalli S, et al., 2021)

The Emerging Significance of LIF/LIFR in Cancer

The LIF/LIFR axis plays a multifaceted role in cancer, impacting growth, invasion, metastasis, immune regulation, and therapy resistance. In pancreatic ductal adenocarcinoma (PDAC), LIF acts as a growth factor and is associated with shorter patient survival. LIF expression in pancreatic tissues is limited to pathological conditions, and circulating LIF levels correlate with treatment responses.

In melanoma, LIFR expression is elevated in highly malignant melanocytic lesions and correlates with poor prognosis. Similarly, LIFR is a novel prognostic biomarker in gallbladder cancer. In prostate cancer, histone methyltransferase KMT2D promotes carcinogenesis and metastasis by activating LIFR expression through epigenetic mechanisms.

During breast cancer progression, the LIF promoter is demethylated, and LIF overexpression enhances proliferation and metastasis. Triple-negative breast cancer (TNBC) exhibits significantly higher LIF and LIFR levels than ER-positive subtypes, and high LIF expression is associated with poor relapse-free survival. Moreover, OSM and LIF secreted by epithelial and stromal cells contribute to tumor progression via autocrine and paracrine mechanisms.

LIFR expression is also elevated in colorectal cancer and osteosarcoma, where it promotes STAT3-mediated invasion and growth. In medulloblastoma, the PI3K p110α subunit regulates LIFRα expression through the c-Myc/miR-125b axis. In prostate cancer, the LIF/LIFR/STAT3 axis maintains PD-L1 protein stability and upregulates genes linked to metastasis.

Importantly, LIF/LIFR exerts cell-type-specific effects, promoting or inhibiting proliferation and survival. In gastric cancer, LIF stimulates proliferation and invasion through the LIFR-Hippo-YAP pathway by inhibiting apoptosis. Interestingly, in some breast cancer cells disseminated to bone, LIFR activates the Hippo-YAP pathway to confer a dormancy phenotype.

These signaling differences are influenced by ligand diversity, varying pathway activation levels, and the tumor microenvironment (TME), collectively resulting in LIF/LIFR acting as a tumor promoter in many solid cancers.

Role of LIF/LIFR in the Tumor Microenvironment (TME)

LIF/LIFR modulates immune cell populations in the TME, including effector T cells, regulatory T cells, macrophages, and myeloid cells, contributing to immune suppression. In tumor-associated macrophages, LIF regulates CXCL9 and prevents CD8+ T cell infiltration, impairing the efficacy of anti-PD1 immunotherapy. Combining LIF neutralizing antibodies with PD1 inhibition can restore immune responses and improve survival outcomes.

In ovarian cancer, LIF is secreted by tumor cells and mesenchymal stem cells (MSCs), contributing to immune evasion in the peritoneal cavity. In endometrial cancer, obesity-related factors such as estrogen and leptin upregulate LIF, LIFR, and phosphorylated STAT3 in endometrial cells, promoting tumor progression. LIF signaling also facilitates fibroblast activation and tumor-stroma crosstalk.

LIF is induced under hypoxic conditions and by TGF-β, which enhances glioma stem cell renewal via SMAD-mediated LIF expression. An autocrine LIF/LIFR/STAT loop in fibroblasts sustains inflammation and promotes a tumor-permissive environment.

Role of LIF/LIFR in Stemness and Therapy Resistance

LIF/LIFR signaling is increasingly recognized as a key regulator of cancer stem cells (CSCs), which are resistant to therapy and responsible for tumor relapse. The LIF-STAT3 axis governs stem cell self-renewal and maintains expression of pluripotency factors such as SOX2 and NANOG.

In early metastatic niches, bone marrow-derived MSCs secrete LIF to activate the ERK/STAT3 axis, promoting mesenchymal-to-epithelial transition (MET) and supporting metastatic colonization. In breast cancer, TGF-β induces CSC self-renewal via the ILEI/LIFR axis. In glioblastoma, TGF-β/LIF signaling prevents differentiation and sustains the stemness of glioma-initiating cells.

These findings collectively highlight the central role of the LIF/LIFR axis in tumorigenesis, immune modulation, metastasis, and therapeutic resistance, making it an attractive target for cancer treatment strategies.

References

  1. Tang W, Ramasamy K, Pillai SMA, et al. LIF/LIFR oncogenic signaling is a novel therapeutic target in endometrial cancer. Cell Death Discov. 2021;7(1):216.
  2. Halder S, Parte S, Kshirsagar P, et al. The Pleiotropic role, functions, and targeted therapies of LIF/LIFR axis in cancer: Old spectacles with new insights. Biochim Biophys Acta Rev Cancer. 2022;1877(4):188737.
  3. Viswanadhapalli S, Dileep KV, Zhang KYJ, et al. Targeting LIF/LIFR signaling in cancer. Genes Dis. 2021 Apr 29;9(4):973-980.
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