KLK8 promotes the proliferation and metastasis of colorectal cancer via the activation of EMT associated with PAR1

Hua, Qing; Sun, Zhirong; Liu, Yi; Shen, Xuefang; Zhao, Weiwei; Zhu, Xiaoyan; Xu, Pingbo

doi:10.1038/s41419-021-04149-x

Cited by 26 publications

(18 citation statements)

References 70 publications

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“…KLK8 has high expression in a variety of tumors including pancreatic and colorectal cancer. In experimental mouse models, KLK8 overexpression had both pro-proliferative and anti-apoptotic effects [49, 50]. The FKBP4 gene is a member of the immunophilin protein family, which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking.…”

Section: Resultsmentioning

confidence: 99%

Distinct cell states define the developmental trajectories of mucinous appendiceal neoplasms towards pseudomyxoma metastases

Ayala

Sathe

Bai

et al. 2022

Preprint

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Objective: Appendiceal mucinous neoplasms (AMN) start in the appendix. Following appendiceal perforation, these tumor metastasize, leading to pseudomyxoma peritonei (PMP). We characterized the distinct cell types and states of AMN and PMP. Design: Single-cell RNA-seq was conducted on 31 samples including AMNs, PMP metastases and a subset of matched normal appendix or omental tissues. We validated the findings with immunohistochemistry, mass spectrometry on malignant ascites from PMP patients and gene expression data from an independent set of 63 PMPs. Results: AMNs and PMPs had epithelial tumor cells with goblet features including the elevated expression of mucin genes. Among these tumors, we identified developmental cell states of the epithelium that ranged from progenitor phase to goblet cell differentiation. Metastatic PMP cells had a distinct cell state with gene expression signatures indicative of mTOR and RAS signaling pathways. A series of cancer genes defined this metastatic cell state. Matched PMP metastases from the same patient differed in their expression signatures. The cell state signatures were validated in external datasets containing 63 PMP patients. AMN and PMP tumor microenvironment (TME) contained CD4 T follicular helper-like cells and cytotoxic CD8 T cells. Conclusion: AMN and PMP tumors consisted of progenitor epithelial cells that differentiate into goblet cells. PMP cells had a distinct cell state indicative of metastasis. The TME was infiltrated with T cells, suggesting that immunotherapy is a potential treatment.

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Section: Resultsmentioning

confidence: 99%

Distinct cell states define the developmental trajectories of mucinous appendiceal neoplasms towards pseudomyxoma metastases

Ayala

Sathe

Bai

et al. 2022

Preprint

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“…KLK8 induced colorectal cancer development by triggering EMT [256]. The wound healing and Transwell migration assays revealed that KLK8 promoted cell proliferation, invasion and metastasis [256]. The upregulation was also associated with metastasis of head and neck SCC to cervical lymph nodes [257].…”

Section: Metastasis-regulated Differentially Expressed Genesmentioning

confidence: 99%

“…Kallikrein-related peptidase 8 (KLK8) is one such protein that has been identified to be highly expressed in cervical, ovarian and endometrial cancers, indicating that it could be a viable target for therapy [254,255]. KLK8 induced colorectal cancer development by triggering EMT [256]. The wound healing and Transwell migration assays revealed that KLK8 promoted cell proliferation, invasion and metastasis [256].…”

Section: Metastasis-regulated Differentially Expressed Genesmentioning

confidence: 99%

Multidimensional outlook on the pathophysiology of cervical cancer invasion and metastasis

et al. 2023

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Cervical cancer being one of the primary causes of high mortality rates among women is an area of concern, especially with ineffective treatment strategies. Extensive studies are carried out to understand various aspects of cervical cancer initiation, development and progression; however, invasive cervical squamous cell carcinoma has poor outcomes. Moreover, the advanced stages of cervical cancer may involve lymphatic circulation with a high risk of tumor recurrence at distant metastatic sites. Dysregulation of the cervical microbiome by human papillomavirus (HPV) together with immune response modulation and the occurrence of novel mutations that trigger genomic instability causes malignant transformation at the cervix. In this review, we focus on the major risk factors as well as the functionally altered signaling pathways promoting the transformation of cervical intraepithelial neoplasia into invasive squamous cell carcinoma. We further elucidate genetic and epigenetic variations to highlight the complexity of causal factors of cervical cancer as well as the metastatic potential due to the changes in immune response, epigenetic regulation, DNA repair capacity, and cell cycle progression. Our bioinformatics analysis on metastatic and non-metastatic cervical cancer datasets identified various significantly and differentially expressed genes as well as the downregulation of potential tumor suppressor microRNA miR-28-5p. Thus, a comprehensive understanding of the genomic landscape in invasive and metastatic cervical cancer will help in stratifying the patient groups and designing potential therapeutic strategies.

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“…In another d-flow-related study, ( Li F. et al, 2021 ) also found that d-flow induced EC transformation into pro-atherogenic phenotypes. Several EC subsets have been identified, which highly express Klk8 (a secretory serine protease, acting as an oncogene or anti-oncogene in various tumors and associated with learning and memory), Lrp1(LDL receptor-related protein 1, associated with lipid homeostasis, clearance of apoptotic cells and metabolism of amyloid-β peptides), Dkk2 (dickkopf WNT signaling pathway inhibitor 2, related to angiogenesis) and Cd36 (a scavenger receptor associated with lipid metabolism) respectively, namely Klk8 hi , Lrp1 hi , Dkk2 hi , and Cd36 hi ECs ( Endemann et al, 1993 ; Min et al, 2011 ; Shinohara et al, 2017 ; Li J. et al, 2021 ; Hua et al, 2021 ). Klk8 hi and Lrp1 hi ECs are mainly derived from non-PCL carotid arteries, whereas Dkk2 hi and Cd36 hi ECs are d-flow-derived EC subsets.…”

Section: Scrna-seq Applications In Atherosclerosis Researchmentioning

confidence: 99%

Single-cell RNA sequencing in atherosclerosis: Mechanism and precision medicine

Wang

Zhang

et al. 2022

Front. Pharmacol.

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Atherosclerosis is the pathological basis of various vascular diseases, including those with high mortality, such as myocardial infarction and stroke. However, its pathogenesis is complex and has not been fully elucidated yet. Over the past few years, single-cell RNA sequencing (scRNA-seq) has been developed and widely used in many biological fields to reveal biological mechanisms at the cellular level and solve the problems of cellular heterogeneity that cannot be solved using bulk RNA sequencing. In this review, we briefly summarize the existing scRNA-seq technologies and focus on their application in atherosclerosis research to provide insights into the occurrence, development and treatment of atherosclerosis.

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KLK8 promotes the proliferation and metastasis of colorectal cancer via the activation of EMT associated with PAR1

Cited by 26 publications

References 70 publications

Distinct cell states define the developmental trajectories of mucinous appendiceal neoplasms towards pseudomyxoma metastases

Distinct cell states define the developmental trajectories of mucinous appendiceal neoplasms towards pseudomyxoma metastases

Multidimensional outlook on the pathophysiology of cervical cancer invasion and metastasis

Single-cell RNA sequencing in atherosclerosis: Mechanism and precision medicine

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