High-fat diet induced cyclophilin B enhances STAT3/lncRNA-PVT1 feedforward loop and promotes growth and metastasis in colorectal cancer

Abstract

High-fat diet (HFD) has been implicated to promote colorectal cancer (CRC). Recently, oncogene Cyclophilin B (CypB) is reported to be induced by cholesterol. However, the role of CypB in CRC carcinogenesis and metastasis associated with HFD remains unknown. In the present study, we showed that HFD-induced CypB enhances proliferation and metastasis through an inflammation-driven circuit, including Signal Transducer and Activator of Transcription 3 (STAT3)-triggered transcription of lncRNA-PVT1, and its binding with CypB that promotes activation of STAT3. CypB was found to be upregulated in CRC, which was correlated with elevated body mass index and poor prognosis. HFD induced CypB expression and proinflammatory cytokines in colon of mice. Besides, CypB restoration facilitated growth, invasion and metastasis in CRC cells both in vitro and in vivo. Moreover, RIP sequencing data identified lncRNA-PVT1 as a functional binding partner of CypB. Mechanistically, PVT1 increased the phosphorylation and nuclear translocation of STAT3 in response to IL-6, through directly interaction with CypB, which impedes the binding of Suppressors Of Cytokine Signalling 3 (SOCS3) to STAT3. Furthermore, STAT3 in turn activated PVT1 transcription through binding to its promoter, forming a regulatory loop. Finally, this CypB/STAT3/PVT1 axis was verified in TCGA datasets and CRC tissue arrays. Our data revealed that CypB linked HFD and CRC malignancy by enhancing the CypB/STAT3/PVT1 feedforward axis and activation of STAT3.

Chaga mushroom extract suppresses oral cancer cell growth via inhibition of energy metabolism

“…STAT3 is a key regulator of cancer progression 32 , 33 . The STAT3 signaling pathway participates in cell proliferation in several types of cancers, such as liver, breast, colorectal, gastric, and lung cancers 34 .…”

Role of STAT3 in cancer cell epithelial‑mesenchymal transition (Review)

“…Indeed, several studies have revealed that PVT1 is an EMT inducer (52,53,(184)(185)(186)(187). Furthermore, STAT3 was also shown to upregulate PVT1 expression through binding to its promoter (14) and therefore, PVT1 and STAT3 form a positive regulatory loop to enhance cancer progression. Taken together, PVT1 has been demonstrated to participate in the regulation of the STAT3-EMT signaling axis.…”

“…Epithelial-mesenchymal transition (EMT) is a cellular program that drives plasticity during embryogenesis, wound healing and cancer progression (9). In various types of cancer, EMT has been shown to be associated with a large variety of cancer features, including tumor cell stemness (9), metastasis (9), cancer metabolism (10,11), immune evasion (9,12) and drug resistance (9), in addition to adaptation to the microenvironment (9,(13)(14)(15)(16). EMT is regulated at multiple levels; physical constraints, hypoxia, inflammation and oncogenic or metabolic stress act at the first level, whereas the activation of signaling pathways, including the WNT, hypoxia-inducible factor (HIF), Notch, transforming growth factor-β (TGF-β), Ras and nuclear factor-κB (NF-κB) pathways, operates at the second level.…”

Deciphering STAT3 signaling potential in hepatocellular carcinoma: tumorigenesis, treatment resistance, and pharmacological significance

“…The presence of a high-fat diet due to cyclophilin B is significant in inducing STAT3 signaling to increase PVT1 expression. Moreover, there is a positive feedback loop between STAT3 and PVT1 that may promote the progression of colorectal tumor cells [ 52 ]. When STAT3 expression increases, it induces YAP signaling to promote lung tumor cell metastasis [ 53 ].…”