TY - JOUR
T1 - The Pleiotropic role, functions and targeted therapies of LIF/LIFR axis in cancer
T2 - Old spectacles with new insights
AU - Halder, Sushanta
AU - Parte, Seema
AU - Kshirsagar, Prakash
AU - Muniyan, Sakthivel
AU - Nair, Hareesh B.
AU - Batra, Surinder K.
AU - Seshacharyulu, Parthasarathy
N1 - Publisher Copyright:
© 2022
PY - 2022/7
Y1 - 2022/7
N2 - The dysregulation of leukemia inhibitory factor (LIF) and its cognate receptor (LIFR) has been associated with multiple cancer initiation, progression, and metastasis. LIF plays a significant tumor-promoting role in cancer, while LIFR functions as a tumor promoter and suppressor. Epithelial and stromal cells secrete LIF via autocrine and paracrine signaling mechanism(s) that bind with LIFR and subsequently with co-receptor glycoprotein 130 (gp130) to activate JAK/STAT1/3, PI3K/AKT, mTORC1/p70s6K, Hippo/YAP, and MAPK signaling pathways. Clinically, activating the LIF/LIFR axis is associated with poor survival and anti-cancer therapy resistance. This review article provides an overview of the structure and ligands of LIFR, LIF/LIFR signaling in developmental biology, stem cells, cancer stem cells, genetics and epigenetics of LIFR, LIFR regulation by long non-coding RNAs and miRNAs, and LIF/LIFR signaling in cancers. Finally, neutralizing antibodies and small molecule inhibitors preferentially blocking LIF interaction with LIFR and antagonists against LIFR under pre-clinical and early-phase pre-clinical trials were discussed.
AB - The dysregulation of leukemia inhibitory factor (LIF) and its cognate receptor (LIFR) has been associated with multiple cancer initiation, progression, and metastasis. LIF plays a significant tumor-promoting role in cancer, while LIFR functions as a tumor promoter and suppressor. Epithelial and stromal cells secrete LIF via autocrine and paracrine signaling mechanism(s) that bind with LIFR and subsequently with co-receptor glycoprotein 130 (gp130) to activate JAK/STAT1/3, PI3K/AKT, mTORC1/p70s6K, Hippo/YAP, and MAPK signaling pathways. Clinically, activating the LIF/LIFR axis is associated with poor survival and anti-cancer therapy resistance. This review article provides an overview of the structure and ligands of LIFR, LIF/LIFR signaling in developmental biology, stem cells, cancer stem cells, genetics and epigenetics of LIFR, LIFR regulation by long non-coding RNAs and miRNAs, and LIF/LIFR signaling in cancers. Finally, neutralizing antibodies and small molecule inhibitors preferentially blocking LIF interaction with LIFR and antagonists against LIFR under pre-clinical and early-phase pre-clinical trials were discussed.
KW - EC359
KW - LIF
KW - LIFR
KW - LIFR-AS1
KW - gp130
UR - http://www.scopus.com/inward/record.url?scp=85131951772&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85131951772&partnerID=8YFLogxK
U2 - 10.1016/j.bbcan.2022.188737
DO - 10.1016/j.bbcan.2022.188737
M3 - Review article
C2 - 35680099
AN - SCOPUS:85131951772
SN - 0304-419X
VL - 1877
JO - Biochimica et Biophysica Acta - Reviews on Cancer
JF - Biochimica et Biophysica Acta - Reviews on Cancer
IS - 4
M1 - 188737
ER -