Xiukun Hou

Tianjin Medical University Cancer Institute and Hospital

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Ming Gao

Tianjin Medical University Cancer Institute and Hospital

Linfei Hu

Tianjin Medical University Cancer Institute and Hospital

Xianhui Ruan

Tianjin Medical University Cancer Institute and Hospital

Jingtai Zhi

Tianjin First Center Hospital

Xiangqian Zheng

Tianjin Medical University Cancer Institute and Hospital

Xiangqian Zheng

Tianjin Medical University Cancer Institute and Hospital

Lizhao Guan

Tianjin Medical University Cancer Institute and Hospital

Yu Wu

Sichuan University

Weiwei Yang

Beijing University of Technology

Songfeng Wei

Tianjin Medical University Cancer Institute and Hospital

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Tianjin Medical University Cancer Institute and Hospital

Tianjin Medical University

Chinese Academy of Sciences

National Clinical Research

University of Chinese Academy of Sciences

Shanghai Jiao Tong University

Nankai University

Peking University

Sun Yat-sen University

Dalian Medical University

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Pharmacological inhibition of Ref-1 enhances the therapeutic sensitivity of papillary thyroid carcinoma to vemurafenib

Cell Death and Disease (2022)

Linfei Hu Jun Zhang Mengran Tian Kang Ning Xu Guangwei

Abstract The use of the BRAF inhibitor vemurafenib exhibits drug resistance in the treatment of thyroid cancer (TC), and finding more effective multitarget combination therapies may be an important solution. In the present study, we found strong correlations between Ref-1 high expression and BRAF mutation, lymph node metastasis, and TNM stage. The oxidative stress environment induced by structural activation of BRAF upregulates the expression of Ref-1, which caused intrinsic resistance of PTC to vemurafenib. Combination inhibition of the Ref-1 redox function and BRAF could enhance the antitumor effects of vemurafenib, which was achieved by blocking the action of Ref-1 on BRAF proteins. Furthermore, combination treatment could cause an overload of autophagic flux via excessive AMPK protein activation, causing cell senescence and cell death in vitro. And combined administration of Ref-1 and vemurafenib in vivo suppressed PTC cell growth and metastasis in a cell-based lung metastatic tumor model and xenogeneic subcutaneous tumor model. Collectively, our study provides evidence that Ref-1 upregulation via constitutive activation of BRAF in PTC contributes to intrinsic resistance to vemurafenib. Combined treatment with a Ref-1 redox inhibitor and a BRAF inhibitor could make PTC more sensitive to vemurafenib and enhance the antitumor effects of vemurafenib by further inhibiting the MAPK pathway and activating the excessive autophagy and related senescence process.

10.1038/s41419-022-04550-0

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PARP inhibitor shuts down the global translation of thyroid cancer through promoting Pol II binding to DIMT1 pause

International Journal of Biological Sciences (2023)

Xiukun Hou Mengran Tian Junya Ning Zhongyu Wang Fengli Guo

Thyroid cancer has become the most frequent endocrine-related malignancy.Currently, a mounting body of evidences support the clinical strategies for extending the benefit of PARP inhibitors beyond BRCA-mutant cancers.However, the functions and molecular mechanisms of PARP inhibitors in thyroid cancers (TCs) are not fully understood.Here, on the one hand, we revealed that niraparib promotes the accumulation of DNA damage in TCs.On the other hand, we indicated that niraparib inhibits the transcription of DIMT1 through promoting Pol II pausing in a PAR-dependent manner, subsequently leading to a global translation inhibition in TCs.Meanwhile, we found that niraparib activates the NF-κB signaling pathway by inhibiting the PARylation of p65, which decreases its ubiquitination and degradation level through E3 ubiquitin ligase RNF146.Moreover, bortezomib (a small molecule inhibitor of the NF-κB signaling pathway) could significantly enhance the anti-tumor effect of niraparib on TCs in vitro and in vivo.Our findings provide mechanistic supports for the efficacy of PARP inhibitors in cancer cells lacking BRCA-mutant.

PARP inhibitor

10.7150/ijbs.81895

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ABCB11 accumulated in immature tertiary lymphoid structures participates in xenobiotic metabolic process and predicts resistance to PD-1/PD-L1 inhibitors in head and neck squamous cell carcinoma

Translational Oncology (2023)

Junya Ning Jie Hao Fengli Guo Xiukun Hou Lijuan Li

Head and neck squamous cell carcinomas (HNSCC) are at a high risk of recurrence and multimodal therapy have not significantly improved survival in recent decades. Although immune checkpoint inhibitors (ICIs) are effective in a small proportion of HNSCC patients, the majority do not respond. In this study, we for the first time revealed that xenobiotic metabolic process was significantly associated with resistance to programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors in HNSCC and found that ATP binding cassette subfamily B member 11 (ABCB11) accumulated in immature tertiary lymphoid structures (TLSs) predicted worse progression-free survival (PFS) and overall survival (OS) after PD-1/PD-L1 inhibitors therapy. Moreover, the expression of cytochrome P450 1A2 (CYP1A2), a cytochrome P450 (CYP) enzyme that participates in xenobiotic metabolic process, was significantly upregulated in CD45+ABCB11+ tumor-infiltrating lymphocytes (TILs) compared with CD45+ABCB11-TILs in HNSCC tissues. Whole slide scans of 110 HNSCC tissues with hematoxylin-eosin (HE) and multispectral immuno-fluorescent (mIF) staining revealed that ABCB11 had a high co-expression with CYP1A2 in immature TLSs, and colocalization of ABCB11 and CYP1A2 in immature TLs significantly associated with high infiltration of immunosuppressive T-regulatory (Treg). Our study revealed that ABCB11 accumulated in immature TLSs might upregulate CYP1A2 to mediate xenobiotic metabolic process, thus increase the immunosuppressive Treg infiltration, and induce resistance to PD-1/PD-L1 inhibitors in HNSCC.

10.1016/j.tranon.2023.101747

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LDHA induces EMT gene transcription and regulates autophagy to promote the metastasis and tumorigenesis of papillary thyroid carcinoma

Cell Death and Disease (2021)

Xiukun Hou Xianle Shi Wei Zhang Dapeng Li Linfei Hu

Papillary thyroid carcinoma (PTC) is one of the most common kinds of endocrine-related cancer and has a heterogeneous prognosis. Metabolic reprogramming is one of the hallmarks of cancers. Aberrant glucose metabolism is associated with malignant biological behavior. However, the functions and mechanisms of glucose metabolism genes in PTC are not fully understood. Thus, data from The Cancer Genome Atlas database were analyzed, and lactate dehydrogenase A (LDHA) was determined to be a potential novel diagnostic and therapeutic target for PTCs. The research objective was to investigate the expression of LDHA in PTCs and to explore the main functions and relative mechanisms of LDHA in PTCs. Higher expression levels of LDHA were found in PTC tissues than in normal thyroid tissues at both the mRNA and protein levels. Higher expression levels of LDHA were correlated with aggressive clinicopathological features and poor prognosis. Moreover, we found that LDHA not only promoted PTC migration and invasion but also enhanced tumor growth both in vitro and in vivo. In addition, we revealed that the metabolic products of LDHA catalyzed induced the epithelial-mesenchymal transition process by increasing the relative gene H3K27 acetylation. Moreover, LDHA knockdown activated the AMPK pathway and induced protective autophagy. An autophagy inhibitor significantly enhanced the antitumor effect of FX11. These results suggested that LDHA enhanced the cell metastasis and proliferation of PTCs and may therefore become a potential therapeutic target for PTCs.

Lactate dehydrogenase A

Reprogramming

10.1038/s41419-021-03641-8

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Citations (68)

METTL3 inhibition induced by M2 macrophage-derived extracellular vesicles drives anti-PD-1 therapy resistance via M6A-CD70-mediated immune suppression in thyroid cancer

Cell Death and Differentiation (2023)

Junya Ning Xiukun Hou Jie Hao Wei Zhang Yi Shi

Immune checkpoint

10.1038/s41418-023-01217-x

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Citations (32)

NSUN2-mediated m⁵C modification drives alternative splicing reprogramming and promotes multidrug resistance in anaplastic thyroid cancer through the NSUN2/SRSF6/UAP1 signaling axis

Theranostics (2025)

Xiukun Hou Qiman Dong Jie Hao Min Liu Junya Ning

Reprogramming

Anaplastic thyroid cancer

10.7150/thno.104713

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Diagnostic accuracy of ultrasound superb microvascular imaging for parotid tumors：A protocol for systematic review and meta-analysis

Jili Zhang Jialing Wu Xiukun Hou

10.37766/inplasy2020.10.0093

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2017 年第二版 NCCN 甲状腺肿瘤指南解读

Clinical Oncology and Cancer Research (2018)

Xiangqian Zheng Xiukun Hou Ming Gao

10.3969/j.issn.1000-8179.2018.01.046

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Targeting SHP2 sensitizes differentiated thyroid carcinoma to the MEK inhibitor.

PubMed (2022)

Jingtai Zhi Jiaoyu Yi Xiukun Hou Wei Wang Weiwei Yang

Pharmacologic targeting of components of the MAPK/ERK pathway in differentiated thyroid carcinoma (DTC) is often limited due to the development of adaptive resistance. However, the detailed mechanism of MEK inhibitor (MEKi) resistance is not fully understood. Here, MEKi-resistant models were constructed successfully, in which multiple receptor tyrosine kinases (RTKs) signaling pathways and Src-homology 2 domain-containing phosphatase 2 (SHP2) were activated in MEKi-resistant cells. Given the physiological role of SHP2 as the downstream target of many RTKs, we first found blockade of SHP2 enhanced the sensitivity to MEKi in constructed MEKi-resistant models. Interestingly, we also found that compared with MEKi treatment alone, MEKi in combination with an SHP2 inhibitor markedly suppressed the reactivation of the MEK/ERK pathway; thus, the addition of the SHP2 inhibitor significantly improved the antitumor effects of MEKi. The synergistic suppression of DTC upon treatment with both inhibitors was further confirmed in xenograft models and transgenic models. Thus, our data suggest that RTKs activation leads to reactivation of the MAPK pathway and resistance to MEKi in DTC, which is reversed by SHP2 blockade. As a novel active inhibitor of SHP2, SHP099 in combination with MEKi is a promising therapeutic approach for advanced DTC and MEKi-resistant one.

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METTL3 is a Potential Prognostic Biomarker in Head and Neck Squamous Cell Carcinoma

Research Square (Research Square) (2022)

Lijuan Li Yu Zeng Xiukun Hou Gaojian Zhuang Weijing Hao

Abstract The authors have requested that this preprint be removed from Research Square.

10.21203/rs.3.rs-1440953/v1

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