CELL DEATH AND DIFFERENTIATION
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2025
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IF 15.4
Wang Xiaolu,Wang Qianqian,Wang Hong,Cai Guodi,An Yana,Liu Peiqing,Zhou Huihao,Chen Hong-Wu,Ji Shufeng,Ye Jiantao,Wang Junjian
Clinical treatment options for triple-negative breast cancer (TNBC) are currently limited to chemotherapy because of a lack of effective therapeutic targets. Recent evidence suggests that long noncoding RNAs (lncRNAs) encode bioactive peptides or proteins, thereby playing noncanonical yet significant roles in regulating cellular processes. However, the potential of lncRNA-translated products in cancer progression remains largely unknown. In this study, we identified a previously undocumented small protein encoded by the lncRNA LINC02870 . This protein is localized at the endoplasmic reticulum (ER) and participates in ER stress, thus, we named it the endoplasmic reticulum stress protein (ERSP). ERSP was highly expressed in TNBC tissues, and elevated LINC02870 content was correlated with poor prognosis in TNBC patients. Loss of ERSP inhibited TNBC growth and metastasis both in vitro and in vivo. The pro-oncogenic effects of ERSP could be attributed to its selective activation of the IRE1α/XBP1s branch. ERSP enhances the unfolded protein response (UPR) by interacting with XBP1s, facilitating the nuclear accumulation of XBP1s, thereby promoting the expression of ER stress-related genes. These findings highlight the regulatory role of the lncRNA-encoded protein ERSP in ER stress and suggest that it is a potential therapeutic target for TNBC.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
ONCOGENE
·
2024
·
IF 6.9
Zhang Tingting,Zhao Faming,Hu Yanxia,Wei Jinlan,Cui Fengzhen,Lin Yahang,Jin Yang,Sheng Xia
Humans are widely exposed to phthalates, a major chemical plasticizer that accumulates in the liver. However, little is known about the impact of chronic phthalate exposure on liver cancer development. In this study, we applied a long-term cell culture model by treating the liver cancer cell HepG2 and normal hepatocyte L02 to environmental dosage of monobutyl phthalate (MBP), the main metabolite of phthalates. Interestingly, we found that long-term MBP exposure significantly accelerated the growth of HepG2 cells in vitro and in vivo, but barely altered the function of L02 cells. MBP exposure triggered reprogramming of lipid metabolism in HepG2 cells, where cholesterol accumulation subsequently activated the IRE1α-XBP1s axis of the unfolded protein response. As a result, the XBP1s-regulated gene sets and pathways contributed to the increased aggressiveness of HepG2 cells. In addition, we also showed that MBP-induced cholesterol accumulation fostered an immunosuppressive microenvironment by promoting tumor-associated macrophage polarization toward the M2 type. Together, these results suggest that environmental phthalates exposure may facilitate liver cancer progression, and alerts phthalates exposure to patients who already harbor liver tumors.
研究领域:
毒理学
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癌症生物学
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代谢学
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免疫学
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PubMed
高影响因子
ONCOGENE
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2024
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IF 6.9
Zhang Tingting,Zhao Faming,Zhang Yi,Shi Ji-Hua,Cui Fengzhen,Ma Weixiang,Wang Kai,Xu Chuanrui,Zeng Qingping,Zhong Rong,Li Ningning,Liu Yong,Jin Yang,Sheng Xia
Liver-specific Ern1 knockout impairs tumor progression in mouse models of hepatocellular carcinoma (HCC). However, the mechanistic role of IRE1α in human HCC remains unclear. In this study, we show that XBP1s, the major downstream effector of IRE1α, is required for HCC cell survival both in vitro and in vivo. Mechanistically, XBP1s transactivates LEF1, a key co-factor of β-catenin, by binding to its promoter. Moreover, XBP1s physically interacts with LEF1, forming a transcriptional complex that enhances classical Wnt signaling. Consistently, the activities of XBP1s and LEF1 are strongly correlated in human HCC and with disease prognosis. Notably, selective inhibition of XBP1 splicing using an IRE1α inhibitor significantly repressed the viability of tumor explants as well as the growth of tumor xenografts derived from patients with distinct Wnt/LEF1 activities. Finally, machine learning algorithms developed a powerful prognostic signature based on the activities of XBP1s/LEF1. In summary, our study uncovers a key mechanistic role for the IRE1α-XBP1s pathway in human HCC. Targeting this axis could provide a promising therapeutic strategy for HCC with hyperactivated Wnt/LEF1 signaling.
研究领域:
癌症生物学
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分子生物学
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遗传学
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转化医学
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高影响因子
CELLULAR & MOLECULAR BIOLOGY LETTERS
·
2026
·Vol. 31
·期 1
·33
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IF 12.2
Ding Ying,Feng Ziyang,Chen Guanjun,Liu Yunqing,Zhu Yuxing,Cao Ke
Background Anaplastic thyroid cancer (ATC) is a highly aggressive malignancy with rapid progression and poor prognosis. Although N1-methyladenosine (m 1 A) modification has been implicated in cancer development, the specific role of tRNA m 1 A modification in ATC remains unclear. Methods An integrated multi-omics approach is employed, including m 1 A-MAP-tRNA-seq, tRNA-seq, RNA-seq, and Ribo-seq, complemented by functional assays such as tRNA aminoacylation assay, puromycin intake assay, and L-HPG staining. Additional experiments involved polysome profiling qRT-PCR, codon-switch assay, endoplasmic reticulum (ER)-tracker and TPE-MI staining, transmission electron microscopy, ChIP-qPCR, dual-luciferase reporter assay, and BODIPY staining to elucidate the underlying mechanism. Results TRMT6/TRMT61A is significantly upregulated in ATC. The complex promotes tumor cell proliferation and metastasis by enhancing the aminoacylation of specific tRNAs, thereby facilitating global protein translation. Elevated translation led to the accumulation of unfolded proteins in the ER, which activates the IRE1α–XBP1s pathway. Notably, m 1 A modification also increased IRE1α translation, further amplifying the pathway. Activation of the IRE1α–XBP1s pathway upregulates DGAT1 expression, which promotes triglyceride synthesis. Conclusions Together, these findings reveal a previously unrecognized mechanism by which TRMT6/TRMT61A drives ATC progression through translational and metabolic reprogramming, identifying TRMT6/TRMT61A as a promising therapeutic target in ATC. Graphical abstract
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高影响因子
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