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. 2026 Jan 28;17:348. doi: 10.1007/s12672-026-04530-2

Oxaliplatin upregulates Cyr61 expression by inhibiting the Hippo-YAP pathway which contributes to drug resistance of colorectal cancer cells

Pingxia Lu 1,#, Cuifeng Zheng 2,#, Jingling Zhang 1,#, Xianjin Zhu 1, Xianqiang Chen 2, Junrong Zhang 2, Yingping Cao 1,✉, Zhengyuan Huang 2,✉
PMCID: PMC12923716  PMID: 41606217

Abstract

Background

Oxaliplatin (OXA) resistance poses a significant challenge to the efficacy of chemotherapy for advanced colorectal cancer (CRC). This study aimed to elucidate the role of OXA in regulating Cysteine-rich protein 61 (Cyr61) expression via the Hippo-Yes-associated protein (YAP) pathway in the context of chemotherapy-induced drug resistance.

Methods

We used Cell Counting Kit-8 to detect cell viability and proliferation. Expression of Cyr61 was determined by quantitative real-time PCR, western blotting (WB) and Enzyme-linked immunosorbent assay in CRC cell lines. The mechanism of OXA in regulating Cyr61 expression was studied by WB and co-immunoprecipitation.

Results

The results revealed that exposure to varying concentrations of OXA for 24 h induced increased mRNA and protein levels of Cyr61 in HCT8 and HCT116 CRC cells. Mechanistically, OXA-mediated overexpression of Cyr61 in CRC cells was attributed to inhibition of the Hippo-YAP pathway.

Conclusions

These findings provide novel insights into the mechanisms underlying chemotherapy-induced drug resistance in CRC and highlight the release of Cyr61 by CRC cells as a potential therapeutic target for overcoming OXA resistance in CRC.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12672-026-04530-2.

Keywords: Cysteine-rich protein 61, Colorectal cancer, Oxaliplatin, Resistance, Chemotherapy stress

Introduction

Colorectal cancer (CRC) is the third most prevalent malignancy worldwide, with the second highest mortality rate [1]. China has the highest burden of new CRC cases and deaths globally, with an escalating incidence predominantly observed among younger individuals [2]. Radical surgical resection remains the primary therapeutic approach for CRC, whereas chemotherapy is of paramount significance for the intermediate and advanced stages. Despite advancements, 25%–30% of patients with CRC experience recurrence and metastasis post-surgery. Adjuvant chemotherapy, whether administered pre- or post-operatively, has demonstrated efficacy in reducing recurrence rates and enhancing survival outcomes [3].

Oxaliplatin (OXA) is a third-generation platinum-based anticancer drug that induces various forms of cell death, including immunogenic cell death and pyroptosis, by modulating the immune system [4]. Although currently positioned as the frontline agent in CRC chemotherapy, OXA nevertheless encounters resistance in approximately 50% of patients with CRC, posing a substantial impediment to treatment efficacy [5]. Hence, elucidating the mechanisms underlying OXA resistance, overcoming this resistance in CRC cells, and augmenting OXA chemotherapy sensitivity have emerged as critical imperatives for the clinical management of CRC.

Chemotherapy stress refers to the response elicited in tumor cells and the surrounding tissues upon exposure to chemotherapeutic agents. This response involves the synthesis and secretion of various substances, including cytokines, growth factors, and anti-apoptotic proteins, into the microenvironment. These factors create a supportive milieu, often likened to an “umbrella,” fostering tumor cell survival and resistance [6, 7]. Previous investigations of drug resistance mechanisms in CRC have focused predominantly on aberrations in cellular drug pumps, gene mutations, and DNA damage repair pathways. However, the intricate mechanisms underlying drug resistance and relapse induced by chemotherapeutic drug stress remain largely unknown.

Cysteine-rich protein 61 (Cyr61/CCN1), a member of the CCN (Cyr61/CTGF/NOV) family, is a secreted matrix protein [8]. Previous investigations have revealed elevated expression levels of Cyr61 in OXA-resistant CRC cell lines compared to their parental counterparts, with a concomitant correlation observed between Cyr61 expression and OXA resistance [9]. However, the precise factors contributing to the heightened Cyr61 expression in OXA-resistant CRC cells, and the regulatory mechanisms governing this phenomenon, remain elusive.

The Hippo-Yes-associated protein (YAP) pathway represents a remarkably conserved signaling cascade across evolutionary scales. This pathway is pivotal in orchestrating organ size regulation, and engaging in critical biological phenomena, including cell proliferation, differentiation, and apoptosis [10, 11]. Previous studies have underscored the role of Hippo-YAP in modulating Cyr61 involvement in tumor cell proliferation, differentiation, and apoptosis [12–14].

This study sought to analyze the potential induction of Cyr61 production in CRC cells by chemotherapy stress while concurrently exploring the molecular intricacies underlying the role of the Hippo-YAP pathway in inducing Cyr61 expression. This investigation aims to elucidate novel insights into the pathophysiological mechanisms underlying phenomena such as drug resistance or relapse during CRC treatment. Furthermore, it seeks to furnish a potential experimental framework for mitigating drug resistance.

Materials and methods

Cell culture

Human CRC cell lines (HCT8 and HCT116) (both from Meisen Cell Biology Co., Ltd Shanghai, China) were maintained in Dulbecco’s modified Eagles medium (DMEM) (Hyclone, Logan, UT, USA) supplemented with 10% fetal bovine serum and 1% (v/v) penicillin/streptomycin (both from Gibco, Carlsbad, CA, USA) in a humidified atmosphere containing 5% CO2 at 37 ℃.

Preparation of OXA

OXA (Selleck, Houston, TX, USA) was dissolved in sterilized double distilled water at a concentration of 10 mM and stored at −20℃ before use. The OXA solution was filtered through a 0.22 μm filter before storage and diluted to the proper concentration before each experiment.

Cell viability assay

To determine the effect of OXA on the growth of HCT8 and HCT116 cells, the cells were cultured in DMEM containing different concentrations of OXA for 24 h. Cell viability was measured using the Cell Counting Kit-8 (CCK8; Beyotime Biotechnology, Jiangsu, China) assay according to the manufacturer’s instructions. In brief, 5.0 × 103 cells were seeded into each well of a 96-well plate for 48 h, and 10 µL of the CCK8 reagent were added into each well for another 2 h. Then, the optical density of each well was determined at 450 nm using a microplate reader (BioTek, Winooski, VT, USA), and the half-maximal inhibitory concentration (IC50) values for OXA in each cell line were obtained. Each sample was assayed in triplicate, and the experiments were repeated three times.

Quantitative real-time polymerase chain reaction (qRT-PCR)

To analyze the mRNA level of Cyr61, qRT-PCR was performed as described previously [9, 15, 16]. Briefly, total RNA was extracted from cells using TRIzol reagent (Invitrogen, Carlsbad, CA, USA) according to the manufacturer’s instructions. cDNA was synthesized from total RNA using the RevertAid First Strand cDNA Synthesis Kit (Thermo Scientific, Waltham MA, USA). QRT-PCR was performed using the SYBR Green Master Mix (Applied Biosystems, Foster City, CA, USA). The primers used in this study have been described previously [9, 15, 16]. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) served as the internal control gene, and the expression of Cyr61 was evaluated using the 2−∆∆Ct method.

Western blot (WB) analyses and co-immunoprecipitation (CO-IP)

For WB and CO-IP, cells were treated with OXA at different concentrations and times. The cells were lysed at 4 ℃ using cell lysis buffer (Beyotime Biotechnology, Jiangsu, China) for 1 h, then centrifuged at 12,000 g for 10 min. The supernatants were collected and the total protein concentrations were measured using a bicinchoninic acid protein assay kit (Beyotime Biotechnology). Total proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), followed by standard WB. The primary antibodies, all from Cell Signaling Technology (Danvers, MA, USA), were as follows: GAPDH (#5174), CYR61 (#14479), TEAD1 (#12292), and the Hippo Signaling Antibody Sampler Kit (#8579) containing phospho-YAP (Ser397), LATS1, phospho-MOB1, MOB1, Mst1, Mst2, SAV1, phospho-YAP (Ser127), and YAP/transcriptional coactivator with PDZ-binding motif (TAZ). The secondary antibodies were also purchased from Cell Signaling Technology (#7074). For CO-IP, HCT8 cells were lysed, and the supernatants were incubated with anti-TEAD1 and protein A/G agarose (ACE Biotechnology, Hunan, China; #AM001). The immune complexes were subjected to SDS-PAGE and analyzed by WB.

Enzyme-linked immunosorbent assay (ELISA)

To analyze the level of Cyr61 in the cell culture supernatant, a human Cyr61 ELISA kit (R&D Systems, Minneapolis, MN, USA) was used as described previously [9, 15, 16]. ELISA results are adjusted based on the number of cells measured.

Statistical analyses

Prism (version 5.0; GraphPad Software, San Diego, CA, USA) or SPSS (version 21.0; IBM, Armonk, NY, USA) software were used for statistical analyses. All experiments were conducted in triplicate. Non-parametric statistical analyses were utilized. The Mann-Whitney U test was applied for comparative analysis between two groups. On the other hand, when comparing three or more groups, the Kruskal-Wallis test was utilized. Error bars in the figure legends indicate the standard deviation. A value of P < 0.05 was considered to indicate statistical significance.

Results

Effect of OXA on HCT8 and HCT116 cell growth

Two CRC cell lines, HCT8 and HCT116, were used to investigate the effects of OXA on cell growth. The CCK8 assay revealed that the IC50 values of OXA in HCT8 and HCT116 cells were 13.45 ± 1.28 and 7.77 ± 0.41 µg/mL, respectively (Fig. 1).

Fig. 1.

Fig. 1

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Inhibition of growth and IC50s of OXA against HCT8 and HCT116 cells. A, B HCT8 and HCT116 cells were treated with increasing concentrations of OXA for 48 h and analyzed using the CCK8 assay. C The IC50 values of OXA in HCT8 and HCT116 cells were calculated using GraphPad Prism 5.0 software. OXA, oxaliplatin; IC50, half-maximal inhibitory concentration; CCK8, Cell Counting Kit-8

OXA promotes the expression of Cyr61 in HCT8 and HCT116 cells

In HCT8 cells, varying concentrations of OXA elicited an increase in Cyr61 mRNA expression, with the highest level observed at 10 µg/mL (Fig. 2A). Similarly, in HCT116 cells, Cyr61 mRNA expression peaked at 6 µg/mL (Fig. 2D). WB analyses of HCT8 and HCT116 cells after treatment with the aforementioned maximally effective drug concentrations for 24 h revealed a significant increase in Cyr61 protein expression (Fig. 2B, E). Similarly, ELISA assessment of the supernatants from HCT8 and HCT116 cells treated with OXA for 48 and 72 h demonstrated a notable increase in Cyr61 protein levels, particularly in the 72 h group (Fig. 2C, F). Collectively, these findings indicate that OXA promotes Cyr61 expression in CRC cells.

Fig. 2.

Fig. 2

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OXA induces the expression of Cyr61 in HCT8 and HCT116 cells. A, D HCT8 and HCT116 cells were treated with different OXA concentrations for 48 h, and the mRNA level of Cyr61 was detected by qRT-PCR. B, E HCT8 and HCT116 cells were treated with 10 and 6 µg/mL OXA, respectively, for 24 h and the protein level of Cyr61 was detected by western blotting. C, F HCT8 and HCT116 cells were treated with 10 and 6 µg/mL OXA, respectively, for 72 h, and the concentration of Cyr61 in the cell supernatant was determined by an ELISA. *P < 0.05, **P < 0.01. OXA, oxaliplatin; ELISA, enzyme-linked immunosorbent assay

The Hippo-YAP signaling pathway is involved in OXA-induced expression of Cyr61 in HCT8 and HCT116 cells

The levels of components of the Hippo-YAP signaling pathway were detected by WB. Compared with the control group, the levels of SAV1, MST2, LATS1, MOB1, phosphorylated (P)-YAP(Ser127) in HCT8 cells were significantly decreased (P < 0.05), while the levels of YAP-TAZ and TEAD1 were significantly increased (P < 0.05) after a 24 h treatment with 10 µg/mL OXA (Fig. 3). This effect was also observed in HCT116 cells treated with 6 µg/mL OXA for 24 h (Fig. 4). These results indicate that OXA can inhibit the Hippo-YAP signaling pathway in CRC cells, and that the Hippo-YAP signaling pathway may be involved in the induction of Cyr61 by OXA.

Fig. 3.

Fig. 3

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Inhibition of the Hippo-YAP pathway in HCT8 cells treated with 10 µg/mL OXA for 24 h. Representative western blot profiles from a single pair are shown (left). The graph on the right shows the values for three different pairs. *P < 0.05. OXA, oxaliplatin

Fig. 4.

Fig. 4

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Inhibition of the Hippo-YAP pathway in HCT116 cells treated with 6 µg/mL OXA for 24 h. Representative western blot profiles from a single pair are shown (left). The graph on the right shows the values for three different pairs. *P < 0.05. OXA, oxaliplatin

The Hippo-YAP signaling pathway is part of the molecular mechanism of OXA-induced Cyr61 in HCT8 and HCT116 cells

Pretreatment of HCT8 cells for 2 h with verteporfin, a specific inhibitor of the Hippo-YAP pathway known to act by impeding YAP-TEAD binding, followed by the addition of OXA (10 µg/mL), resulted in a notable decrease in Cyr61 mRNA expression compared to the control group (P < 0.05) (Fig. 5A). These findings suggest that OXA modulates Cyr61 expression in HCT8 cells through the Hippo-YAP signaling pathway.

Fig. 5.

Fig. 5

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The Hippo-YAP signaling pathway is involved in OXA-induced expression of Cyr61 in CRC cells. A HCT8 cells were pretreated with verteporfin (10 µM) for 2 h, then treated with OXA (10 µg/mL) for 48 h. Cyr61 mRNA was detected by qRT-PCR. B CO-IP shows TEAD1 binding to Cyr61. C Schematic of the underlying interaction mechanism for OXA regulating Cyr61 expression in CRC cells. qRT-PCR, quantitative real time polymerase chain reaction; OXA, oxaliplatin; CRC, colorectal cancer; CO-IP, co-immunoprecipitation

The WB analyses (Figs. 3 and 4) revealed alterations in key molecules of the Hippo-YAP signaling pathway under the influence of OXA, indicating its inhibitory effect on this pathway in CRC cells. This observation suggests the potential involvement of the Hippo-YAP signaling pathway in the induction of Cyr61 by chemotherapy drugs. A CO-IP assay using HCT8 cells confirmed the binding of the transcription factor TEAD1 to Cyr61 (Fig. 5B). Collectively, these findings support the hypothesis that OXA contributes to drug resistance in CRC by regulating Cyr61 expression via the Hippo-YAP pathway (Fig. 5C).

Discussion

OXA, a prominent third-generation platinum-based drug, is frequently associated with neurotoxicity and other adverse effects. Nonetheless, it remains widely utilized as first-line and combination therapy for CRC, particularly in cases of advanced tumor resection and CRC metastasis [17, 18]. Despite its efficacy, many tumor cells develop resistance to OXA through either primary mechanisms or acquired means to evade its cytotoxic effects. In our study, we observed up-regulation of Cyr61 expression in CRC cells under OXA-induced chemotherapeutic stress. Furthermore, we found that this increase in Cyr61 expression was mediated by the Hippo-YAP pathway.

Cyr61, a critical extracellular matrix-associated protein, exhibits increased expression across various tumor types where it not only promotes tumor cell proliferation and invasiveness, but also contributes to drug resistance in cancers such as kidney and pancreatic [19–21] Our previous investigations underscored the significant upregulation of Cyr61 levels in OXA-resistant CRC cells [9]. Moreover, elevated Cyr61 expression has been shown to effectively shield CRC cells from OXA-induced apoptosis by upregulating Bcl-xL expression, thereby impeding the apoptotic response of CRC cells to OXA chemotherapy [9]. However, the origin of the heightened Cyr61 expression remained unclear.

In 2010, Gilbert et al. [22] reported that daunorubicin induced liver cancer cells to release interleukin-6 into the microenvironment, causing drug resistance in these cells. Similarly, vincristine induced P-glycoprotein-mediated resistance in lung cancer cells [23]. These findings emphasize the notion that the stress response elicited by chemotherapy diminishes the cytotoxic effects of chemotherapeutic drugs on tumor cells, thereby reducing treatment efficacy and fostering tumor resistance and relapse.

In recent years, drug resistance induced by chemotherapy stress has garnered increasing attention, highlighting the capacity of chemotherapy drugs to promote the production of soluble molecules, such as matrix proteins, growth factors, and cytokines, that shield tumor cells from the lethal effects of chemotherapy drugs [22, 24, 25]. The present study demonstrated that OXA stimulates an increase in Cyr61 mRNA and protein expression in CRC cells, with Cyr61 mRNA expression escalating proportionally with the drug concentration. These findings suggest that OXA-induced Cyr61 production in CRC cells further contributes to the augmented Cyr61 levels observed in these cells.

Recently, the Hippo-YAP signaling pathway has emerged as a pivotal determinant of chemotherapy resistance in various human malignancies [26–28]. The core kinases of the Hippo pathway, including MST1/2, SAV1, LATS1/2, and MOB1, orchestrate a cascade of phosphorylation events that regulate the transcriptional activities of key effectors, namely YAP and TAZ [11]. YAP, a central molecule downstream of the Hippo pathway, is phosphorylated, which enhances its binding affinity for 14-3-3 chaperone proteins. This leads to the cytoplasmic retention and subsequent degradation of P-YAP, precluding its nuclear translocation and transcriptional activation. Conversely, unphosphorylated YAP translocates into the nucleus and associates with the transcription factors TEAD1-4 (members of the TEA domain family), thereby promoting the expression of target genes such as CTGF, CDK6, and Cyr61 [29].

Our findings demonstrated that OXA activates YAP by downregulating the levels of MST1/2, SAV1, LATS1/2, MOB1, and P-YAP proteins in CRC cells. This activation facilitates the nuclear translocation of YAP, which forms a complex with TAZ and binds to TEAD1, thereby initiating downstream gene transcription. Further support for the role of the Hippo-YAP pathway in mediating OXA-induced Cyr61 production in CRC cells was provided by a CO-IP assay that confirmed an interaction between TEAD1 and Cyr61. Overall, these findings elucidated the mechanism by which OXA promotes Cyr61 production in CRC cells via the Hippo-YAP pathway.

This study has several limitations. First, our investigation focused on the effect of OXA chemotherapy stress on Cyr61 expression in CRC cell lines. However, other commonly used CRC treatment regimens, such as 5-fluorouracil and leucovorin, were not evaluated. It remains unclear whether chemotherapeutic pressure from these agents also influences Cyr61 expression, necessitating further investigation. Second, our findings regarding the mechanisms driving Cyr61 overexpression were derived from experiments conducted on two CRC cell lines. Extending our analysis to encompass a broader spectrum of CRC cell lines and, ideally, clinical samples, is essential to elucidate the relationship between Cyr61 levels and drug resistance in patients with CRC. Addressing these limitations will provide a more comprehensive understanding of the role of Cyr61 in CRC resistance to chemotherapy.

Conclusions

Our study demonstrates that OXA induces Cyr61 production in CRC cells, potentially contributing to the heightened Cyr61 levels observed in OXA-resistant CRC cell lines. Importantly, this induction of Cyr61 appears to be mediated through inhibition of the Hippo-YAP pathway by chemotherapeutic stress. These findings not only extend our understanding of the impact of chemotherapy stress, but also offer a novel perspective for investigating the mechanisms underlying drug resistance induced by chemotherapy stress. Further research in this area holds promise for elucidating new strategies to overcome drug resistance in CRC and enhance the efficacy of chemotherapy.

Supplementary Information

Supplementary Material 1 (2.6MB, rar)

Acknowledgements

We would like to thank Editage (www.editage.cn) for English language editing.

Abbreviations

CRC

Colorectal cancer

Cyr61

Cysteine-rich protein 61

DMEM

Dulbecco’s modified Eagles medium

GAPDH

Glyceraldehyde 3-phosphate dehydrogenase

OXA

Oxaliplatin

qRT-PCR

Quantitative real time-polymerase chain reaction

TAZ

Transcriptional coactivator with PDZ-binding motif

YAP

Yes-associated protein

Author contributions

P.X. L and Z.Y. H wrote the original draft and participated in reviewing and editing the manuscript. C.F. Z, J.L. Z, and J.R. Z conducted the experiments. X.Q. C performed the formal analysis and interpretation of data. X.J. Z managed the project administration. Y.P. C provided supervision and oversight throughout the research. All authors reviewed the manuscript.

Funding

This work was supported by Fujian provincial health technology project [grant number: 2021GGA015 to Zhengyuan Huang]; Fujian Provincial Natural Science Foundation of China [grant number: 2024J01596 to Pingxia Lu]; the Joint Funds for the Innovation of Science and Technology, Fujian province [grant number: 2020Y9088 to Pingxia Lu, grant number: 2025Y9375 to Zheng-yuan Huang]; Startup Fund for Scientific Research, Fujian Medical University [grant number: 2023QH1057 to Jingling Zhang].

Data availability

The data that support the findings of this study are available from the corresponding author, Yingping Cao and Zhengyuan Huang, upon reasonable request. Corresponding to Yingping Cao and Zhengyuan Huang when necessary.

Declarations

Ethics approval and consent to participate

Not required.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Pingxia Lu, Cuifeng Zheng and Jingling Zhang contributed equally to this work.

Contributor Information

Yingping Cao, Email: caoyingping@aliyun.com.

Zhengyuan Huang, Email: huangzy@fjmu.edu.cn.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material 1 (2.6MB, rar)

Data Availability Statement

The data that support the findings of this study are available from the corresponding author, Yingping Cao and Zhengyuan Huang, upon reasonable request. Corresponding to Yingping Cao and Zhengyuan Huang when necessary.

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