TIMP-2 regulates 5-Fu resistance via the ERK/MAPK signaling pathway in colorectal cancer

et al. 2022

Aging

The roles of asparagine-linked glycosylation (ALG) members in tumorigenic process have been widely explored. However, their effects in colorectal cancer progression are still confusing. Here, we screened 12 ALGs' expression through online datasets and found that ALG10 was mostly upregulated in colorectal cancer tissues. We found that ALG10 knockdown significantly suppressed the expression of stemness markers, ALDH activity, and sphere-formation ability. In vivo tumorigenic analysis indicated that ALG10 knockdown attenuated the tumor-initiating ability and chemoresistance of colorectal cancer cells. Further mechanistic studies showed that ALG10 knockdown suppressed the activity of TGF-β signaling by reducing TGFBR2 glycosylation, which was necessary for ALG10-mediated effects on colorectal cancer stemness; Conversely, TGF-β signaling activated ALG10 gene promoter activity through Smad2's binding to ALG10 gene promoter and TGF-β signaling promoted the stemness of colorectal cancer cells in an ALG10-dependent manner. This work identified a novel ALG10/TGF-β positive regulatory loop responsible for colorectal cancer stemness.

Section: Discussionmentioning

confidence: 99%

A novel ALG10/TGF-β positive regulatory loop contributes to the stemness of colorectal cancer

et al. 2022

Aging

“…Further study also shows that dasatinib exhibits modest antitumor effect only when combined with chemotherapy in CRC PDX 88 . It is reported that TIMP‐2 (tissue inhibitor of matrix metalloproteinase‐2) is upregulated in 5‐Fu‐resistant CRC PDX, and inhibition of TIMP‐2 using an anti‐TIMP‐2 antibody or ERK/MAPK (extracellular regulated protein kinase/mitogen‐activated protein kinase) inhibition by U0126 suppresses TIMP‐2‐mediated 5‐Fu‐resistance 89 . The ATM (ataxia telangiectasia‐mutated gene) inhibitor, AZ31, exhibits antitumor activity in CRC PDX resistant to irinotecan monotherapy 90 .…”

Section: The Application Of Pdx In Crc Researchmentioning

confidence: 99%

“…88 It is re- U0126 suppresses TIMP-2-mediated 5-Fu-resistance. 89 The ATM (ataxia telangiectasia-mutated gene) inhibitor, AZ31, exhibits antitumor activity in CRC PDX resistant to irinotecan monotherapy. 90 Alisertib, an inhibitor of aurora kinases, shows antitumor activity in combination with cetuximab or irinotecan.…”

Section: Drug Discoverymentioning

confidence: 99%

“… 88 It is reported that TIMP‐2 (tissue inhibitor of matrix metalloproteinase‐2) is upregulated in 5‐Fu‐resistant CRC PDX, and inhibition of TIMP‐2 using an anti‐TIMP‐2 antibody or ERK/MAPK (extracellular regulated protein kinase/mitogen‐activated protein kinase) inhibition by U0126 suppresses TIMP‐2‐mediated 5‐Fu‐resistance. 89 The ATM (ataxia telangiectasia‐mutated gene) inhibitor, AZ31, exhibits antitumor activity in CRC PDX resistant to irinotecan monotherapy. 90 Alisertib, an inhibitor of aurora kinases, shows antitumor activity in combination with cetuximab or irinotecan.…”

Section: The Application Of Pdx In Crc Researchmentioning

confidence: 99%

See 1 more Smart Citation

Patient‐derived xenograft model in colorectal cancer basic and translational research

Liu

Xin

Anim Models and Exp Med

2022

Colorectal cancer (CRC), one of the most deadly cancers, is the fourth most common cause of cancer-related deaths. 1 Currently, surgery is the main treatment option for primary and metastatic CRC, and chemotherapy and targeted drugs are regularly used as adjuvant regimens. [2][3][4] Despite improvements in screening and treatment, the number of individuals newly diagnosed is increasing rapidly. Moreover, metastasis, recurrence, and chemoresistance are common in CRC patients after treatment, which leads to the dismal prognosis and high mortality of CRC patients. [5][6][7] These issues lead to the need for more advancements in CRC treatment. About 5% of CRCs are hereditary tumor syndromes, such as familial adenomatous polyposis (FAP) and Lynch syndrome. 8 Most of the CRCs are sporadic as the comprehensive effects of various factors, including somatic genetic alterations, chronic inflammation, lifestyle, and environmental stimuli. 9 These genetic and nongenetic risk factors work together to promote CRC development and progression. [10][11][12][13] To date, the mechanisms involved in the interactions of these factors driving CRC development and progression are

“…The extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway is activated in numerous cancers, including lung cancer, and is involved in regulating the proliferation, survival, invasion, apoptosis and drug resistance of cancer cells (9)(10)(11). In addition to being overactivated by RAS proteins, the ERK/MAPK signaling pathway is also overactivated by the α subtype of protein kinase C (PKCα) in cancer (12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

PPP1R14D promotes the proliferation, migration and invasion of lung adenocarcinoma via the PKCα/BRAF/MEK/ERK signaling pathway

Cao

et al. 2022

Int J Oncol

Protein phosphatase 1 (PP1) inhibitors play a role in tumor progression through different mechanisms. Protein phosphatase 1 regulatory subunit 14D (PPP1R14D) is an inhibitor of PP1. However, the role of PPP1R14D in tumors and its mechanism of action are largely unknown. The purpose of the present study was to investigate the expression, function and mechanism of PPP1R14D in lung adenocarcinoma (LUAD). In the present study, GEPIA database analysis and immunohistochemistry demonstrated that PPP1R14D was highly expressed in LUAD tissues and that the expression of PPP1R14D in LUAD was negatively correlated with the age of patients and positively correlated with the 8th American Joint Committee on Cancer staging among patients. In addition, Kaplan-Meier Plotter database analysis showed that PPP1R14D expression was associated with lower survival rates in patients with LUAD. PPP1R14D knockdown significantly inhibited LUAD cell proliferation, migration and invasion and induced LUAD cell arrest at the G1 phase of the cell cycle. Mechanistic analyses revealed that PPP1R14D knockdown may inhibit cell proliferation, migration and invasion by inactivating PKCα/BRAF/MEK/ERK pathway signaling and its downstream key proteins c-Myc/Cyclin E1-CDK2 and MMP2/MMP9/Vimentin. Moreover, knockdown of PPP1R14D suppressed tumor growth in vivo. All these results showed that PPP1R14D plays an important role in LUAD tumorigenesis and may serve as a potential prognostic factor and therapeutic target in LUAD.