REG4 is an indicator for KRAS mutant lung adenocarcinoma with TTF-1 low expression

Sun, Si; Hu, Zhihuang; Huang, Shenglin; Ye, Xun; Wang, Jialei; Chang, Jianhua; Wu, Xianghua; Wang, Qifeng; Zhang, Lanlin; Hu, Xiurong; Yu, Hui

doi:10.1007/s00432-019-02988-y

Cited by 10 publications

(12 citation statements)

References 32 publications

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“…As per the microassay-based transcriptional analysis and knockout of all the representative KRAS -inducible genes, knockout of REG4 showed the most significant reduction in spheroid-forming capability in stem cells harboring mutations in both KRAS and APC. Expression of REG4 was significantly upregulated in a mutant KRAS-dependent manner in both colorectal stem cells and cancer tissues harboring APC mutation, consistent with another study with REG4 overexpression in KRAS mutant lung adenocarcinoma ( 13 ). Protein levels of p-LRP6, β -catenin, and p-GSK-3 β were increased upon treatment with recombinant REG4 in a dose-dependent manner.…”

Section: Mechanisms Involved In Human Cancerssupporting

confidence: 90%

“…Serum REG4 levels can be used to predict liver recurrence ( 25 ). Survival analysis revealed that high REG4 expression could be correlated with shortened survival time and emerged as an adverse prognostic factor ( 13 , 45 ). Jared et al.…”

Section: Reg4 Expression Pattern and Clinical Significance In Human Cmentioning

confidence: 99%

“…analyzed 55 clinical samples and combined GEO and TCGA database information, and found that both mRNA and protein levels of REG4 were significantly upregulated in KRAS mutant lung adenocarcinoma samples with low expression of the transcription termination factor 1 (TTF-1) (identified as the KS subgroup). REG4 promotes the progression in KRAS mutant lung adenocarcinoma cells progression and can be used as a novel biomarker in lung adenocarcinoma subtype ( 13 ). Another study also reported overexpression of REG4 in invasive mucinous lung adenocarcinoma of gastric differentiation-type ( 62 ).…”

Section: Reg4 Expression Pattern and Clinical Significance In Human Cmentioning

confidence: 99%

“…Moreover, REG4 was also upregulated in KRAS-mutant lung carcinoma and thus, is a novel biomarker in the lung adenocarcinoma subtype. Silencing REG4 reduced cancer cell proliferation and tumorigenesis in vivo and in vitro by blocking G2/M transition ( 13 ), suggesting an important role of REG4 in KRAS-driven lung cancer pathogenesis. However, further studies are needed to clarify the role and underlying mechanisms of REG4 in cell proliferation and division and its potential therapeutic value in lung cancer.…”

Section: Mechanisms Involved In Human Cancersmentioning

confidence: 99%

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The Clinical Significance and Mechanisms of REG4 in Human Cancers

et al. 2021

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Regenerating islet-derived type 4 (REG4), a member of the calcium-dependent lectin gene superfamily, is abnormally expressed in various cancers, such as colorectal, gastric, gallbladder, pancreatic, ovarian, prostate, and lung cancer. REG4 is associated with a relatively unfavorable prognosis and clinicopathologic features in cancers, including advanced tumor and nodal stage, histological differentiation, and liver and peritoneal metastasis. Moreover, REG4-positive cancer cells show more frequent resistance to chemoradiotherapy, especially 5-FU-based chemotherapy. REG4 participates in many aspects of carcinogenesis, including cell proliferation, apoptosis, cell cycle, invasion, metastasis, and drug resistance. The underlying mechanisms are complex and involve a series of signaling mediators and multiple pathways. Thus, REG4 may be a potential diagnostic and prognostic biomarker as well as a candidate therapeutic target in cancer patients. In this review, we systematically summarize the advances about the clinical significance, biological functions, and mechanisms underlying REG4 in cancer to provide new directions for future cancer research.

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Section: Mechanisms Involved In Human Cancerssupporting

confidence: 90%

Section: Reg4 Expression Pattern and Clinical Significance In Human Cmentioning

confidence: 99%

Section: Reg4 Expression Pattern and Clinical Significance In Human Cmentioning

confidence: 99%

Section: Mechanisms Involved In Human Cancersmentioning

confidence: 99%

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The Clinical Significance and Mechanisms of REG4 in Human Cancers

et al. 2021

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“…Many positive hits (i.e., genes with significantly higher expression in highly metastatic cells) have known roles in potentiating tumorigenicity (Fig. 4C, top); for example, IFI27 is an interferon-induced factor that is anti-apoptotic and promotes epithelial- 15 mesenchymal transition (EMT), cell migration, and cancer stemness in various carcinomas (49,50), REG4 enhances cell migration and invasion in colorectal carcinoma (51) and KRAS-driven lung adenocarcinoma (52), and TNNT1 has elevated expression in many cancers and may promote cell invasion via EMT (53). Similarly, many negative hits (genes with significantly lower expression in highly metastatic cells) have known roles in attenuating metastatic potential (Fig.…”

Section: Transcriptional Signatures Of Distinct Metastatic Phenotypesmentioning

confidence: 99%

Single-cell lineages reveal the rates, routes, and drivers of metastasis in cancer xenografts

Quinn

Jones

Okimoto

et al. 2020

Preprint

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N.Y.).One Sentence Summary: Detailed single-cell phylogenies capture the frequency, tissue routes, and seeding patterns of metastasis in vivo. Abstract:25 2 Consequential events in cancer progression are typically rare and occur in the unobserved past. Detailed cell phylogenies can capture the history and chronology of such transient events -including metastasis. Here, we applied our Cas9-based lineage tracer to study metastatic progression in a lung cancer xenograft mouse model, revealing the underlying rates, routes, and patterns of metastasis. We report deeply resolved phylogenies for tens of thousands of metastatically disseminated cancer cells. We observe surprisingly diverse metastatic phenotypes, 5 ranging from metastasis-incompetent to highly aggressive populations, and these differences are associated with characteristic changes in transcriptional state, including differential expression of metastasis-related genes like IFI27 and ID3. We further show that metastases transit via tissue routes that are diverse, complex, and multidirectional, and identify examples of reseeding, seeding cascades, and parallel seeding topologies. More broadly, we demonstrate the power of next-generation lineage tracers to record cancer evolution at high resolution 10 and vast scale. Main Text:Cancer progression is governed by evolutionary principles (reviewed in (1)), which leave clear phylogenetic signatures upon every step of this process (2, 3), from early acquisition of oncogenic mutations (i.e., the relationships between normal and malignantly transformed cells (4)), to metastatic colonization of distant 15 tissues (i.e., the relationship between the primary tumor and metastases (5)), and finally adaptation to therapeutic challenges (i.e., the relationship between sensitive and resistant clones (6)). Metastasis is a particularly important step in cancer progression to study because it is chiefly responsible for disease relapse and mortality (7). Yet because metastatic events are intrinsically rare, transient, and stochastic (8,9), they are challenging to monitor in real time. Analogous to the cell fate maps that have played an essential role in deepening our understanding of 20 organismal development and cell type differentiation (10, 11), accurately reconstructed phylogenetic trees of tumors and metastases can reveal key features of this process, such as the clonality, timing, frequency, origins, and destinations of metastatic seeding (12).Lineage tracing techniques allow one to map the genealogy of related cells, providing a critical tool for exploring the phylogenetic principles of biological processes like cancer progression and metastasis. Classical

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PSC subtyping based on TTF‐1 and p40 expression reveals distinct molecular characteristics and therapeutic strategies

Dou

Tian

et al. 2022

Intl Journal of Cancer

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Pulmonary sarcomatoid carcinoma (PSC) is a unique form of poorly differentiated nonsmall cell lung cancer (NSCLC) and is notorious for its highly malignant nature and dismal prognosis. To introduce effective treatment for PSC patients, precise subtyping of PSC is demanding. In our study, TTF-1 and P40 immunohistochemistry (IHC) staining were applied to 56 PSC patients with multiomics data. According to IHC results, we categorized these patients into three subgroups and profiled their molecular contexture using bioinformatic skills. IHC results classified these patients into three subgroups: TTF-1 positive subgroup (n = 27), P40 positive subgroup (n = 15) and double-negative subgroup (n = 14). Spindle cell samples accounted for 35.71% (5/14) of double-negative patients, higher than others (P = .034). The three subgroups were heterogeneous in the genomic alteration spectrum, showing significant differences in the RTK/RAS pathway (P = .004) and the cell cycle pathway (P = .030).The methylation profile of the double-negative subgroup was between the other two subgroups. In similarity analysis, the TTF-1 and p40 subgroups were closely related to LUAD and LUSC, respectively. The TTF-1 positive subgroup had the highest leukocyte

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REG4 is an indicator for KRAS mutant lung adenocarcinoma with TTF-1 low expression

Cited by 10 publications

References 32 publications

The Clinical Significance and Mechanisms of REG4 in Human Cancers

The Clinical Significance and Mechanisms of REG4 in Human Cancers

Single-cell lineages reveal the rates, routes, and drivers of metastasis in cancer xenografts

PSC subtyping based on TTF‐1 and p40 expression reveals distinct molecular characteristics and therapeutic strategies

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