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      PTPRO represses colorectal cancer tumorigenesis and progression by reprogramming fatty acid metabolism

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          Abstract

          Background

          Abnormal expression of protein tyrosine phosphatases (PTPs) has been reported to be a crucial cause of cancer. As a member of PTPs, protein tyrosine phosphatase receptor type O (PTPRO) has been revealed to play tumor suppressive roles in several cancers, while its roles in colorectal cancer (CRC) remains to be elucidated. Hence, we aimed to explore the roles and mechanisms of PTPRO in CRC initiation and progression.

          Methods

          The influences of PTPRO on the growth and liver metastasis of CRC cells and the expression patterns of different lipid metabolism enzymes were evaluated in vitro and in vivo. Molecular and biological experiments were conducted to uncover the underpinning mechanisms of dysregulated de novo lipogenesis and fatty acid β‐oxidation.

          Results

          PTPRO expression was notably downregulated in CRC liver metastasis compared to the primary cancer, and such a downregulation was associated with poor prognosis of patients with CRC. PTPRO silencing significantly promoted cell growth and liver metastasis. Compared with PTPRO wild‐type mice, PTPRO‐knockout mice developed more tumors and harbored larger tumor loads under treatment with azoxymethane and dextran sulfate sodium. Gene set enrichment analysis revealed that PTPRO downregulation was significantly associated with the fatty acid metabolism pathways. Blockage of fatty acid synthesis abrogated the effects of PTPRO silencing on cell growth and liver metastasis. Further experiments indicated that PTPRO silencing induced the activation of the AKT serine/threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling axis, thus promoting de novo lipogenesis by enhancing the expression of sterol regulatory element‐binding protein 1 (SREBP1) and its target lipogenic enzyme acetyl‐CoA carboxylase alpha (ACC1) by activating the AKT/mTOR signaling pathway. Furthermore, PTPRO attenuation decreased the fatty acid oxidation rate by repressing the expression of peroxisome proliferator‐activated receptor alpha (PPARα) and its downstream enzyme peroxisomal acyl‐coenzyme A oxidase 1 (ACOX1) via activating the p38/extracellular signal‐regulated kinase (ERK) mitogen‐activated protein kinase (MAPK) signaling pathway.

          Conclusions

          PTPRO could suppress CRC development and metastasis via modulating the AKT/mTOR/SREBP1/ACC1 and MAPK/PPARα/ACOX1 pathways and reprogramming lipid metabolism.

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          Cancer statistics, 2022

          Rebecca Siegel, Kimberly D Miller, Hannah Fuchs … (2022)
          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes. Incidence data (through 2018) were collected by the Surveillance, Epidemiology, and End Results program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2019) were collected by the National Center for Health Statistics. In 2022, 1,918,030 new cancer cases and 609,360 cancer deaths are projected to occur in the United States, including approximately 350 deaths per day from lung cancer, the leading cause of cancer death. Incidence during 2014 through 2018 continued a slow increase for female breast cancer (by 0.5% annually) and remained stable for prostate cancer, despite a 4% to 6% annual increase for advanced disease since 2011. Consequently, the proportion of prostate cancer diagnosed at a distant stage increased from 3.9% to 8.2% over the past decade. In contrast, lung cancer incidence continued to decline steeply for advanced disease while rates for localized-stage increased suddenly by 4.5% annually, contributing to gains both in the proportion of localized-stage diagnoses (from 17% in 2004 to 28% in 2018) and 3-year relative survival (from 21% to 31%). Mortality patterns reflect incidence trends, with declines accelerating for lung cancer, slowing for breast cancer, and stabilizing for prostate cancer. In summary, progress has stagnated for breast and prostate cancers but strengthened for lung cancer, coinciding with changes in medical practice related to cancer screening and/or treatment. More targeted cancer control interventions and investment in improved early detection and treatment would facilitate reductions in cancer mortality.
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            Hallmarks of Cancer: New Dimensions

            Douglas Hanahan (2022)
            The hallmarks of cancer conceptualization is a heuristic tool for distilling the vast complexity of cancer phenotypes and genotypes into a provisional set of underlying principles. As knowledge of cancer mechanisms has progressed, other facets of the disease have emerged as potential refinements. Herein, the prospect is raised that phenotypic plasticity and disrupted differentiation is a discrete hallmark capability, and that nonmutational epigenetic reprogramming and polymorphic microbiomes both constitute distinctive enabling characteristics that facilitate the acquisition of hallmark capabilities. Additionally, senescent cells, of varying origins, may be added to the roster of functionally important cell types in the tumor microenvironment. SIGNIFICANCE: Cancer is daunting in the breadth and scope of its diversity, spanning genetics, cell and tissue biology, pathology, and response to therapy. Ever more powerful experimental and computational tools and technologies are providing an avalanche of "big data" about the myriad manifestations of the diseases that cancer encompasses. The integrative concept embodied in the hallmarks of cancer is helping to distill this complexity into an increasingly logical science, and the provisional new dimensions presented in this perspective may add value to that endeavor, to more fully understand mechanisms of cancer development and malignant progression, and apply that knowledge to cancer medicine.
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              Cancer statistics in China and United States, 2022: profiles, trends, and determinants

              Changfa Xia, Xuesi Dong, He. Li … (2022)
              Background: The cancer burden in the United States of America (USA) has decreased gradually. However, China is experiencing a transition in its cancer profiles, with greater incidence of cancers that were previously more common in the USA. This study compared the latest cancer profiles, trends, and determinants between China and USA. Methods: This was a comparative study using open-source data. Cancer cases and deaths in 2022 were calculated using cancer estimates from GLOBOCAN 2020 and population estimates from the United Nations. Trends in cancer incidence and mortality rates in the USA used data from the Surveillance, Epidemiology, and End Results program and National Center for Health Statistics. Chinese data were obtained from cancer registry reports. Data from the Global Burden of Disease 2019 and a decomposition method were used to express cancer deaths as the product of four determinant factors. Results: In 2022, there will be approximately 4,820,000 and 2,370,000 new cancer cases, and 3,210,000 and 640,000 cancer deaths in China and the USA, respectively. The most common cancers are lung cancer in China and breast cancer in the USA, and lung cancer is the leading cause of cancer death in both. Age-standardized incidence and mortality rates for lung cancer and colorectal cancer in the USA have decreased significantly recently, but rates of liver cancer have increased slightly. Rates of stomach, liver, and esophageal cancer decreased gradually in China, but rates have increased for colorectal cancer in the whole population, prostate cancer in men, and other seven cancer types in women. Increases in adult population size and population aging were major determinants for incremental cancer deaths, and case-fatality rates contributed to reduced cancer deaths in both countries. Conclusions: The decreasing cancer burden in liver, stomach, and esophagus, and increasing burden in lung, colorectum, breast, and prostate, mean that cancer profiles in China and the USA are converging. Population aging is a growing determinant of incremental cancer burden. Progress in cancer prevention and care in the USA, and measures to actively respond to population aging, may help China to reduce the cancer burden.
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                Author and article information

                Contributors
                Shaobo Mo: shaobom@126.com
                Qingguo Li: oncosurgeonli@sohu.com
                Guoxiang Cai:
                ORCID: https://orcid.org/0000-0003-2953-3460
                gxcai@fudan.edu.cn
                Journal
                Journal ID (nlm-ta): Cancer Commun (Lond)
                Journal ID (iso-abbrev): Cancer Commun (Lond)
                Journal ID (doi): 10.1002/(ISSN)2523-3548
                Journal ID (publisher-id): CAC2
                Title: Cancer Communications
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Electronic): 2523-3548
                Publication date (Electronic): 29 July 2022
                Publication date Collection: September 2022
                Volume: 42
                Issue: 9 ( doiID: 10.1002/cac2.v42.9 )
                Pages: 848-867
                Affiliations
                [ 1 ] Department of Colorectal Surgery Fudan University Shanghai Cancer Center Shanghai 200032 P. R. China
                [ 2 ] Department of Oncology Shanghai Medical College Fudan University Shanghai 200032 P. R. China
                [ 3 ] Department of Surgery Sixth Affiliated Hospital of Sun Yat‐sen University Guangzhou Guangdong 528406 P. R. China
                Author notes
                [*] [* ] Correspondence

                Guoxiang Cai, MD, PhD., Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032, China.

                Email: gxcai@ 123456fudan.edu.cn

                Qingguo Li, MD, PhD., Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032, China.

                Email: oncosurgeonli@ 123456sohu.com

                Shaobo Mo, MD, PhD., Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032, China.

                Email: shaobom@ 123456126.com

                [†]

                These authors contributed equally to this work

                Author information
                https://orcid.org/0000-0003-2953-3460
                Article
                Publisher ID: CAC212341
                DOI: 10.1002/cac2.12341
                PMC ID: 9456702
                PubMed ID: 35904817
                SO-VID: ac69790c-3dc3-4044-bab7-c001217bb6e5
                Copyright © © 2022 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat‐sen University Cancer Center.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date revision received : 22 March 2022
                Date received : 22 March 2022
                Date accepted : 11 July 2022
                Page count
                Figures: 8, Tables: 0, Pages: 20, Words: 9040
                Funding
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Award ID: 81871958
                Award ID: 82103554
                Funded by: Science and Technology Commission of Shanghai Municipality , doi 10.13039/501100003399;
                Award ID: 19140902100
                Award ID: 16401970502
                Award ID: 17411951100
                Categories
                Subject: Original Article
                Subject: Original Articles
                Custom metadata
                source-schema-version-number 2.0
                cover-date September 2022
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.8 mode:remove_FC converted:08.09.2022

                Keywords: akt,colorectal cancer,fatty acid oxidation,fatty acid synthesis,lipid metabolism,liver metastasis,mtor,ptpro,tumorigenesis
                Data availability:
                Keywords: akt, colorectal cancer, fatty acid oxidation, fatty acid synthesis, lipid metabolism, liver metastasis, mtor, ptpro, tumorigenesis

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