Noncoding RNAs as regulators of STAT3 pathway in gastrointestinal cancers: Roles in cancer progression and therapeutic response

Ashrafizadeh, Milad; Mohan, Chakrabhavi Dhananjaya; Rangappa, Shobith; Zarrabi, Ali; Hushmandi, Kiavash; Kumar, Alan Prem; Sethi, Gautam; Rangappa, Kanchugarakoppal S.

doi:10.1002/med.21950

Cited by 32 publications

(2 citation statements)

References 440 publications

(791 reference statements)

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“…Accumulating evidence suggests that lncRNAs play a significant role in regulating multiple signaling pathways, offering insights into the development of targeted therapies [ 58 – 63 ]. Currently, BBOX1-AS1 has been confirmed to participate in the regulation of the Hedgehog signaling pathway [ 42 ].…”

Section: Bbox1-as1 Influences the Signaling Pathwaysmentioning

confidence: 99%

A review on the role of gamma-butyrobetaine hydroxylase 1 antisense RNA 1 in the carcinogenesis and tumor progression

Hu,

Liu,

Zhou

et al. 2023

Cancer Cell Int

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Gamma-butyrobetaine hydroxylase 1 antisense RNA 1 (BBOX1-AS1), located on human chromosome 11 p14, emerges as a critical player in tumorigenesis with diverse oncogenic effects. Aberrant expression of BBOX1-AS1 intricately regulates various cellular processes, including cell growth, epithelial–mesenchymal transition, migration, invasion, metastasis, cell death, and stemness. Notably, the expression of BBOX1-AS1 was significantly correlated with clinical-pathological characteristics and tumor prognoses, and it could also be used for the diagnosis of lung and esophageal cancers. Through its involvement in the ceRNA network, BBOX1-AS1 competitively binds to eight miRNAs in ten different cancer types. Additionally, BBOX1-AS1 can directly modulate downstream protein-coding genes or act as an mRNA stabilizer. The implications of BBOX1-AS1 extend to critical signaling pathways, including Hedgehog, Wnt/β-catenin, and MELK/FAK pathways. Moreover, it influences drug resistance in hepatocellular carcinoma. The present study provides a systematic review of the clinical significance of BBOX1-AS1’s aberrant expression in diverse tumor types. It sheds light on the intricate molecular mechanisms through which BBOX1-AS1 influences cancer initiation and progression and outlines potential avenues for future research in this field.

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Section: Bbox1-as1 Influences the Signaling Pathwaysmentioning

confidence: 99%

A review on the role of gamma-butyrobetaine hydroxylase 1 antisense RNA 1 in the carcinogenesis and tumor progression

Hu,

Liu,

Zhou

et al. 2023

Cancer Cell Int

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“…It has been well-documented that suppression of persistent activation of STATs induces apoptosis of cancer cells. Protein tyrosine phosphatases (PTPs), suppressor of cytokine signaling (SOCS), and protein inhibitor of activated STATs (PIAS) are the negative regulators of the STAT pathway, and they are often disrupted in cancers (Ashrafizadeh et al, 2023;Mohan et al, 2021a). Among PTPs, protein tyrosine phosphatase ε (PTPε) has been demonstrated as a negative modulator of the STAT signaling pathway in human cancers.…”

Section: Introductionmentioning

confidence: 99%

A new triazolyl‐indolo‐quinoxaline induces apoptosis in gastric cancer cells by abrogating the STAT3/5 pathway through upregulation of PTPεC

Suresh,

Jung,

Mohan

et al. 2023

Drug Development Research

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Signal transducer and activator of transcription 3 (STAT3) and STAT5 are the transcription factors that have been studied extensively in relevance to the development of cancers in humans. Suppression of either STAT3 or STAT5‐mediated signaling events has been demonstrated to be effective in inducing cytotoxicity in cancer cells. Herein, new hybrids of triazolyl‐indolo‐quinoxaline are synthesized and examined for their effect on the activation of STAT3 and STAT5 pathways in gastric cancer (GC) cells. Among the newly synthesized compounds, 2,3‐difluoro‐6‐((1‐(3‐fluorophenyl)‐1H‐1,2,3‐triazol‐5‐yl)methyl)‐6H‐indolo[2,3‐b]quinoxaline (DTI) displayed selective cytotoxicity against GC cells over their normal counterpart. Flow cytometric analysis, annexin‐V‐fluorescein isothiocyanate staining, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, live and dead assay, and caspase activation experiments suggested DTI as a potent inducer of apoptosis. The mechanistic approach revealed that DTI imparts cytotoxicity via downregulating the phosphorylation of STAT3Y705 and STAT5Y694/699. DTI significantly reduced the nuclear pool of STAT3/STAT5 and reduced the DNA interaction ability of STAT3/STAT5 as evidenced by immunofluorescence and electrophoretic mobility shift assay. Further investigation revealed that inhibitory effects towards STAT proteins were mediated through the suppression of upstream kinases such as JAK1, JAK2, and Src. Treatment of GC cells with pervanadate counteracted the DTI‐driven STAT3/STAT5 inhibition suggesting the involvement of tyrosine phosphatase. Upon DTI exposure, there was a significant upregulation in the mRNA and protein expression of PTPεC, which is a negative regulator of the JAK‐STAT pathway. Knockdown of PTPεC suppressed the DTI‐induced STATs inhibition in GC cells. Taken together, triazolyl‐indolo‐quinoxaline is presented as a new inhibitor of the STAT3/STAT5 pathway in GC cells.

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Kaempferide triggers apoptosis and paraptosis in pancreatic tumor cells by modulating the ROS production, SHP‐1 expression, and the STAT3 pathway

Jung,

Son,

Mohan

et al. 2024

IUBMB Life

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Pancreatic cancer is one of the deadliest diseases with a poor prognosis and a five‐survival rate. The STAT3 pathway is hyperactivated which contributes to the sustained proliferative signals in pancreatic cancer cells. We have isolated kaempferide (KF), an O‐methylated flavonol, from the green propolis of Mimosa tenuiflora and examined its effect on two forms of cell death namely, apoptosis and paraptosis. KF significantly increased the cleavage of caspase‐3 and PARP. It also downmodulated the expression of Alix (an intracellular inhibitor of paraptosis) and increased the expression of CHOP and ATF4 (transcription factors that promote paraptosis) indicating that KF promotes apoptosis as well as paraptosis. KF also increased intracellular reactive oxygen species (ROS) suggesting the perturbance of the redox state. N‐acetylcysteine reverted the apoptosis‐ and paraptosis‐inducing effects of KF. Some ROS inducers are known to suppress the STAT3 pathway and investigation revealed that KF downmodulates STAT3 and its upstream kinases (JAK1, JAK2, and Src). Additionally, KF also elevated the expression of SHP‐1, a tyrosine phosphatase which is involved in the negative modulation of the STAT3 pathway. Knockdown of SHP‐1 prevented KF‐driven STAT3 inhibition. Altogether, KF has been identified as a promoter of apoptosis and paraptosis in pancreatic cancer cells through the elevation of ROS generation and SHP‐1 expression.

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Noncoding RNAs as regulators of STAT3 pathway in gastrointestinal cancers: Roles in cancer progression and therapeutic response

Cited by 32 publications

References 440 publications

A review on the role of gamma-butyrobetaine hydroxylase 1 antisense RNA 1 in the carcinogenesis and tumor progression

A review on the role of gamma-butyrobetaine hydroxylase 1 antisense RNA 1 in the carcinogenesis and tumor progression

A new triazolyl‐indolo‐quinoxaline induces apoptosis in gastric cancer cells by abrogating the STAT3/5 pathway through upregulation of PTPεC

Kaempferide triggers apoptosis and paraptosis in pancreatic tumor cells by modulating the ROS production, SHP‐1 expression, and the STAT3 pathway

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