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 - Funding Information:
The authors are supported by funding, in parts, by the following grants from the National Institutes of Health/National Cancer Institute (NIH/NCI) Grants U01 CA185148, P01 CA217798, R01 CA247471 , (Dr. Batra), 5 R44 CA235991 (Dr. Nair), Department of Defense Award W81XWH-18-1-0308 (Dr. Batra) and Fred and Pamela Buffett Cancer Center Pilot grant, which NCI supports under award# CA036727 (Dr. Seshacharyulu). In addition, we thank Ramakanth Chirravuri-Venkata for the formal analysis of LIF and LIFR expression in the Mipanda Data portal and Dr. Ponnusamy for Critical review and editing and important intellectual inputs during manuscript preparation. Cartoon figures were generated using BioRender.com acknowledge cBioPortal and Mipanda databases, which were used for LIF and LIFR gene expression and mutation analysis.
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 - gp130
KW - LIF
KW - LIFR
KW - LIFR-AS1
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
VL - 1877
JO - Biochimica et Biophysica Acta - Reviews on Cancer
JF - Biochimica et Biophysica Acta - Reviews on Cancer
SN - 0304-419X
IS - 4
M1 - 188737
ER -