JC

Jung‐Hsuan Chang

National Taiwan University

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Kang‐Yi Su

Zhejiang Ocean University

Wei-Jia Luo

National Taiwan University

Wei-Lun Hsu

National Taiwan University

Eugene C. Lin

National Chung Cheng University

Bu‐Miin Huang

National Cheng Kung University

Hong‐Qing Liu

National Chung Cheng University

Shaw‐Jenq Tsai

National Cheng Kung University

Min-Hui Chien

National Taiwan University

Wen‐Tai Chiu

National Cheng Kung University

Shih‐Chieh Lin

National Cheng Kung University

Cooperative Institutions

National Taiwan University

National Cheng Kung University

National Chung Cheng University

Institute of Biomedical Sciences, Academia Sinica

National Yang Ming Chiao Tung University

National Taiwan University Hospital

National Cheng Kung University Hospital

China Medical University

Institute of Basic Medical Sciences of the Chinese Academy of Medical Sciences

Kaohsiung Medical University

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DNAJB4/HLJ1 deficiency sensitizes diethylnitrosamine-induced hepatocarcinogenesis with peritumoral STAT3 activation

Cell Biology and Toxicology (2024)

Wei-Jia Luo Wei-Lun Hsu Chih-Yun Lu Min-Hui Chien Jung‐Hsuan Chang

Environmental chemicals and toxins are known to impact human health and contribute to cancer developments. Among these, genotoxins induce genetic mutations critical for cancer initiation. In the liver, proliferation serves not only as a compensatory mechanism for tissue repair but also as a potential risk factor for the progression of premalignant lesions. The role of Human Liver DnaJ-Like Protein (DNAJB4/HLJ1), a stress-responsive heat shock protein 40, in genotoxin-induced liver carcinogenesis remains unexplored. Using whole-genome transcriptomic analysis, we demonstrate that HLJ1 deficiency in mice results in altered gene signatures enriched in pathways associated with chemically induced liver cancer and IL-6/STAT3 signaling activation. Employing diethylnitrosamine (DEN) as a carcinogen, we further reveal that STAT3 and H2AX phosphorylation induced by short-term DEN treatment are amplified in HLJ1-deficient mice. In long-term DEN experiments, HLJ1 deletion enhances tumor proliferation and progression, accompanied by pronounced STAT3 phosphorylation in normal tissues rather than in tumor regions. The tumor-suppressive role of peritumoral HLJ1 is validated through the transplantation of HLJ1-wildtype B16F1 and LLC cancer cell lines into syngeneic HLJ1-deficient mice, which exhibits an augmented tumorigenic phenotype compared to wildtype controls. This study uncovers a previously unrecognized role of HLJ1 in suppressing liver carcinogenesis via the downregulation of STAT3 signaling in peritumoral normal cells. These findings suggest that HLJ1 reinforcement represents a promising strategy for liver cancer treatment and prevention.

Liver Cancer

Tumor progression

Tumor initiation

10.1007/s10565-024-09978-y

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High-fat diet induces C-reactive protein secretion, promoting lung adenocarcinoma via immune microenvironment modulation

Disease Models & Mechanisms (2023)

Wei-Lun Hsu Yun-Ting Hsieh Wei-Ming Chen Min-Hui Chien Wei-Jia Luo

To understand the effects of a high-fat diet (HFD) on lung cancer progression and biomarkers, we here used an inducible mutant epidermal growth factor receptor (EGFR)-driven lung cancer transgenic mouse model fed a regular diet (RD) or HFD. The HFD lung cancer (LC-HFD) group exhibited significant tumor formation and deterioration, such as higher EGFR activity and proliferation marker expression, compared with the RD lung cancer (LC-RD) group. Transcriptomic analysis of the lung tissues revealed that the significantly changed genes in the LC-HFD group were highly enriched in immune-related signaling pathways, suggesting that an HFD alters the immune microenvironment to promote tumor growth. Cytokine and adipokine arrays combined with a comprehensive analysis using meta-database software indicated upregulation of C-reactive protein (CRP) in the LC-HFD group, which presented with increased lung cancer proliferation and metastasis; this was confirmed experimentally. Our results imply that an HFD can turn the tumor growth environment into an immune-related pro-tumorigenic microenvironment and demonstrate that CRP has a role in promoting lung cancer development in this microenvironment.

Tumor progression

10.1242/dmm.050360

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ATM‐ and ATR‐induced primary ciliogenesis promotes cisplatin resistance in pancreatic ductal adenocarcinoma

Journal of Cellular Physiology (2022)

Yu‐Ying Chao Bu‐Miin Huang I‐Chen Peng Pei‐Rong Lee Yi‐Shyun Lai

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers because of its late diagnosis and chemoresistance. Primary cilia, the cellular antennae, are observed in most human cells to maintain development and differentiation. Primary cilia are gradually lost during the progression of pancreatic cancer and are eventually absent in PDAC. Here, we showed that cisplatin-resistant PDAC regrew primary cilia. Additionally, genetic or pharmacological disruption of primary cilia sensitized PDAC to cisplatin treatment. Mechanistically, ataxia telangiectasia mutated (ATM) and ATM and RAD3-related (ATR), tumor suppressors that initiate DNA damage responses, promoted the excessive formation of centriolar satellites (EFoCS) and autophagy activation. Disruption of EFoCS and autophagy inhibited primary ciliogenesis, sensitizing PDAC cells to cisplatin treatment. Collectively, our findings revealed an unexpected interplay among the DNA damage response, primary cilia, and chemoresistance in PDAC and deciphered the molecular mechanism by which ATM/ATR-mediated EFoCS and autophagy cooperatively regulate primary ciliogenesis.

Ciliogenesis

10.1002/jcp.30898

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Chemical Exchange Saturation Transfer (CEST) Signal at −1.6 ppm and Its Application for Imaging a C6 Glioma Model

Biomedicines (2022)

Qi-Xuan Wu Hong‐Qing Liu Yi‐Jiun Wang Tsai-Chen Chen Ziying Wei

The chemical exchange saturation transfer (CEST) signal at -1.6 ppm is attributed to the choline methyl on phosphatidylcholines and results from the relayed nuclear Overhauser effect (rNOE), that is, rNOE(-1.6). The formation of rNOE(-1.6) involving the cholesterol hydroxyl is shown in liposome models. We aimed to confirm the correlation between cholesterol content and rNOE(-1.6) in cell cultures, tissues, and animals. C57BL/6 mice (N = 9) bearing the C6 glioma tumor were imaged in a 7 T MRI scanner, and their rNOE(-1.6) images were cross-validated through cholesterol staining with filipin. Cholesterol quantification was obtained using an 18.8-T NMR spectrometer from the lipid extracts of the brain tissues from another group of mice (N = 3). The cholesterol content in the cultured cells was manipulated using methyl-β-cyclodextrin and a complex of cholesterol and methyl-β-cyclodextrin. The rNOE(-1.6) of the cell homogenates and their cholesterol levels were measured using a 9.4-T NMR spectrometer. The rNOE(-1.6) signal is hypointense in the C6 tumors of mice, which matches the filipin staining results, suggesting that their tumor region is cholesterol deficient. The tissue extracts also indicate less cholesterol and phosphatidylcholine contents in tumors than in normal brain tissues. The amplitude of rNOE(-1.6) is positively correlated with the cholesterol concentration in the cholesterol-manipulated cell cultures. Our results indicate that the cholesterol dependence of rNOE(-1.6) occurs in cell cultures and solid tumors of C6 glioma. Furthermore, when the concentration of phosphatidylcholine is carefully considered, rNOE(-1.6) can be developed as a cholesterol-weighted imaging technique.

Filipin

Choline

10.3390/biomedicines10061220

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Role of the cholesterol hydroxyl group in the chemical exchange saturation transfer signal at −1.6 ppm

NMR in Biomedicine (2020)

Yu‐Chi Chang Hong‐Qing Liu Jung‐Hsuan Chang Yu‐Yen Chang Eugene C. Lin

Chemical exchange saturation transfer (CEST) can provide metabolite‐weighted images in the clinical setting; therefore, understanding the origin of each CEST signal is essential to revealing the changes in diseases at the molecular level, which would provide further insight for diagnoses and treatments. The CEST signal at −1.6 ppm is attributed to the choline methyl group of phosphatidylcholines. The methyl groups have no exchangeable protons, so the corresponding CEST signals must result from the relayed nuclear Overhauser effect (rNOE); however, the detailed mechanism remains unclear. Cholesterol is a major component of biological membranes, and its content is closely related to the dynamics and phases of these lipids. However, cholesterol has a hydroxyl group, which could participate in proton exchange to complete the rNOE process. In this study, we used liposomes containing cholesterol and its analogs (5α‐cholestane and progesterone), which presumably have similar capabilities of influencing lipid bilayers, and found that the steroid hydroxyl group is the key to inducing the rNOE at −1.6 ppm. Our results suggest that the origin of the rNOE at −1.6 ppm likely requires an intermolecular NOE between the proton of the choline methyl group and that of the cholesterol hydroxyl group, and a chemical exchange between the cholesterol hydroxyl group and bulk water. However, the phenomenon in which the rNOE at −1.6 ppm appears when the cholesterol concentration is high seems to contradict the in vivo results, suggesting a more complicated mechanism associated with the rNOE at −1.6 ppm in biological membranes.

Choline

Methyl group

10.1002/nbm.4356

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Citations (7)

矛盾追隨行為前因及後果探討;Paradoxical Followership Behaviors : Antecedents and Consequences

張容瑄 Jung‐Hsuan Chang

Followership

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ATM- and ATR-Induced Primary Ciliogenesis Promotes Cisplatin Resistance in Pancreatic Ductal Adenocarcinoma

Research Square (Research Square) (2021)

Yu‐Ying Chao Bu‐Miin Huang I‐Chen Peng Yi‐Shyun Lai Wen‐Tai Chiu

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers because of its late diagnosis and chemoresistance. Primary cilia, the cellular antennae, are observed in most human cells to maintain development and differentiation. Primary cilia are gradually lost during the progression of pancreatic cancer and are eventually absent in PDAC. However, recent study showed that primary cilia regrowth contributes to the development of diverse kinase inhibitor resistance in lung cancer. We elucidated the role of regrowth primary ciliogenesis in PDAC chemoresistance and uncovered the underlying molecular mechanism. Results We showed that cisplatin-resistant PDAC regrew primary cilia. Additionally, genetic or pharmacological disruption of primary cilia sensitized PDAC to cisplatin treatment. Mechanistically, ataxia telangiectasia mutated (ATM) and ATM and RAD3-related (ATR), tumor suppressors that initiate DNA damage responses, promoted the excessive formation of centriolar satellites (EFoCS) and autophagy activation. Disruption of EFoCS and autophagy inhibited primary ciliogenesis, sensitizing PDAC cells to cisplatin treatment. Conclusions Collectively, our findings revealed an unexpected interplay among the DNA damage response, primary cilia, and chemoresistance in PDAC and deciphered the molecular mechanism by which ATM/ATR-mediated EFoCS and autophagy cooperatively regulate primary ciliogenesis.

Ciliogenesis

10.21203/rs.3.rs-942728/v1

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LCRMP-1 is required for spermatogenesis and stabilises spermatid F-actin organization via the PI3K-Akt pathway

Communications Biology (2023)

Jung‐Hsuan Chang Chia‐Hua Chou Jui-Ching Wu Keng-Mao Liao Wei-Jia Luo

Abstract Long-form collapsin response mediator protein-1 (LCRMP-1) belongs to the CRMP family which comprises brain-enriched proteins responsible for axon guidance. However, its role in spermatogenesis remains unclear. Here we find that LCRMP-1 is abundantly expressed in the testis. To characterize its physiological function, we generate LCRMP-1-deficient mice ( Lcrmp-1 −/− ). These mice exhibit aberrant spermiation with apoptotic spermatids, oligospermia, and accumulation of immature testicular cells, contributing to reduced fertility. In the seminiferous epithelial cycle, LCRMP-1 expression pattern varies in a stage-dependent manner. LCRMP-1 is highly expressed in spermatids during spermatogenesis and especially localized to the spermiation machinery during spermiation. Mechanistically, LCRMP-1 deficiency causes disorganized F-actin due to unbalanced signaling of F-actin dynamics through upregulated PI3K-Akt-mTOR signaling. In conclusion, LCRMP-1 maintains spermatogenesis homeostasis by modulating cytoskeleton remodeling for spermatozoa release.

Spermatid

10.1038/s42003-023-04778-2

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Citations (5)