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CHCHD2 as a prognostic biomarker and therapeutic target in lung adenocarcinoma: Insights from pan‑cancer multi‑omics and functional studies

  • Authors:
    • Zikai Xu
    • Jie Shen
    • Yizhou Lin
    • Haotian Shi
    • Cong Zhang
    • Zhengwei Zhang
    • Xiaoyu Zhou
    • Zheng Yang
  • View Affiliations / Copyright

    Affiliations: Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China, Medical School of Nantong University, Nantong, Jiangsu 226001, P.R. China, Department of Pharmacy, Affiliated Hospital of Nantong University, Pharmacy School of Nantong University, Nantong, Jiangsu 226001, P.R. China
    Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 207
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    Published online on: October 15, 2026
       https://doi.org/10.3892/or.2026.9213
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Abstract

Lung adenocarcinoma (LUAD) remains a leading cause of cancer‑related mortality, and mitochondrial proteins have been increasingly implicated in tumor progression. Coiled‑coil‑helix‑coiled‑coil‑helix domain‑containing 2 (CHCHD2) has been reported in several malignancies, yet its pan‑cancer landscape and LUAD‑specific functional relevance have not been comprehensively evaluated. In the present study, multi‑omics analyses were integrated using The Cancer Genome Atlas‑derived datasets and public resources [including Gene Expression Profiling Interactive Analysis (GEPIA) 2, CIBERSORT and CellMiner] to characterize CHCHD2 expression patterns, clinical associations, tumor microenvironment (TME) features, stemness‑related indices and drug‑response correlations across cancers, followed by experimental validation in LUAD models. CHCHD2 was found to be upregulated in multiple cancers and was correlated with advanced disease stage and poor overall survival, especially in patients with LUAD. CHCHD2 promoted cell proliferation and migration while inhibiting apoptosis. CHCHD2 knockdown reduced AKT and ERK phosphorylation and suppressed xenograft tumor growth in vivo. High CHCHD2 expression was associated with increased stemness, an immunosuppressive TME, and differential drug‑response patterns in CellMiner analyses, suggesting that CHCHD2 expression may be associated with compound‑specific sensitivity profiles. Collectively, these findings support an oncogenic role of CHCHD2 in LUAD and highlight its potential utility as a prognostic biomarker and therapeutic target.
View Figures

Figure 1

Pan-cancer expression patterns and
genetic alteration landscape of the CHCHD family. (A) Boxplots
showing the overall mRNA expression distribution of CHCHD family
members (CHCHD1-7 and CHCHD10) across TCGA pan-cancer types. (B)
Heatmap illustrating the relative expression levels of CHCHD family
genes across different cancer types (normalized expression values),
with unsupervised hierarchical clustering applied to both genes and
tumor types. (C) Pairwise expression correlation matrix of CHCHD
family members based on Spearman's correlation analysis; dot size
and color indicate the strength and direction of correlations, with
numerical values representing correlation coefficients. (D)
Differential expression analysis of CHCHD2 between tumor tissues
(red) and corresponding normal tissues (blue) across TCGA cancer
types. (E-H) Pathological stage-associated expression patterns of
CHCHD2 across tumor stages (I–IV), generated using the GEPIA2
‘Stage Plot’ module and evaluated by one-way ANOVA: (E) LUAD, (F)
LIHC, (G) HNSC and (H) KICH. (I) OncoPrint summarizing the spectrum
and frequency of genetic alterations in CHCHD family genes across
10,967 TCGA tumors using cBioPortal. (J) Cancer-type-specific
summary of overall CHCHD family alteration frequencies, indicating
the proportion of tumors harboring at least one CHCHD-family
alteration; copy-number amplification represents the predominant
alteration event. *P<0.05 and ***P<0.001. CHCHD,
coiled-coil-helix-coiled-coil-helix domain; TCGA, The Cancer Genome
Atlas; LUAD, lung adenocarcinoma; LIHC, liver hepatocellular
carcinoma; HNSC, head and neck squamous cell carcinoma; KICH,
kidney chromophobe.

Figure 2

Association between CHCHD2 expression
and OS across multiple cancers (Kaplan-Meier Plotter). (A) In LUAD,
patients with high CHCHD2 expression (red) exhibited poorer OS than
those with low expression (black). (B) In LIHC, patients with high
CHCHD2 expression (red) exhibited poorer OS than those with low
expression (black). (C) In HNSC, patients with high CHCHD2
expression (red) exhibited poorer OS than those with low expression
(black). (D) In BLCA, patients with high CHCHD2 expression (red)
exhibited poorer OS than those with low expression (black). (E) In
ESCA, patients with high CHCHD2 expression (red) exhibited poorer
OS than those with low expression (black). (F) In THYM, high CHCHD2
expression was associated with improved OS. CHCHD,
coiled-coil-helix-coiled-coil-helix domain; OS, overall survival;
LUAD, lung adenocarcinoma; LIHC, liver hepatocellular carcinoma;
HNSC, head and neck squamous cell carcinoma; BLCA, bladder
urothelial carcinoma; ESCA, esophageal carcinoma; THYM, thymoma;
HR, hazard ratio.

Figure 3

CHCHD2 is upregulated in LUAD tissues
and differentially expressed across LUAD cell lines. (A) Western
blot analysis of CHCHD2 protein expression in nine paired LUAD
tumor tissues (T1-T9) and adjacent non-tumorous tissues (N1-N9).
GAPDH was used as the loading control. (B) RT-qPCR analysis of
CHCHD2 mRNA expression in paired LUAD tumor tissues (T) and
adjacent non-tumorous tissues (N). (C) Western blot analysis of
CHCHD2 protein expression in LUAD cell lines, including PC9, A549,
H1299, H1975 and H1650. (D) RT-qPCR analysis of relative CHCHD2
mRNA expression in the indicated LUAD cell lines. Data are
presented as the mean ± SD. ***P<0.001. CHCHD,
coiled-coil-helix-coiled-coil-helix domain; LUAD, lung
adenocarcinoma; RT-qPCR, reverse transcription-quantitative
PCR.

Figure 4

CHCHD2 knockdown suppresses
proliferation and migration and promotes apoptosis in PC9 and H1975
cells. (A and B) Western blot analyses of CHCHD2 knockdown
efficiency in PC9 (A) and H1975 (B) cells transfected with
shCHCHD2-1, shCHCHD2-2, shCHCHD2-3, or negative-control shRNA
(shNC), with corresponding densitometric quantification of CHCHD2
protein expression. (C and D) Reverse transcription-quantitative
PCR analyses of CHCHD2 mRNA expression following transfection with
shNC or the three CHCHD2-targeting shRNAs in H1975 (C) and PC9 (D)
cells. Direct statistical comparisons among the three shRNAs were
performed to evaluate knockdown efficiency. (E and F) CCK-8 assays
showing that CHCHD2 knockdown reduced cell proliferation in PC9 (E)
and H1975 (F) cells. (G) Flow cytometric analysis showing increased
apoptosis following CHCHD2 knockdown in PC9 and H1975 cells. (H)
Wound-healing assay showing reduced migration after CHCHD2
knockdown in PC9 cells. (I) Transwell migration assays showing
reduced migratory ability after CHCHD2 knockdown in PC9 and H1975
cells. (J) Wound-healing assay showing reduced migration after
CHCHD2 knockdown in H1975 cells. White dashed lines indicate the
wound edges used for wound-width measurement. For the CCK-8
time-course data, statistical significance was assessed using
two-way ANOVA followed by Sidak's multiple-comparisons test. Data
are presented as the mean ± SD. *P<0.05, **P<0.01,
***P<0.001 and ****P<0.0001. CHCHD,
coiled-coil-helix-coiled-coil-helix domain; sh-, short hairpin; NC,
negative control; CCK-8, Cell Counting Kit-8; ns, not
significant.

Figure 5

CHCHD2 overexpression promotes
proliferation and migration and inhibits apoptosis in H1299 and
H1650 cells. (A) Western blot and RT-qPCR analyses confirming
CHCHD2 overexpression efficiency in H1299 cells transfected with
CHCHD2-overexpression plasmid (CHCHD2-OE) or NC plasmid. (B)
Western blot and RT-qPCR analyses confirming CHCHD2 overexpression
efficiency in H1650 cells transfected with CHCHD2-OE or NC. (C and
D) CCK-8 assays showing that CHCHD2 overexpression enhanced cell
proliferation in H1299 (C) and H1650 (D) cells. (E) Flow cytometric
analysis showing decreased apoptosis after CHCHD2 overexpression in
H1299 and H1650 cells. (F) Transwell migration assays showing
increased migratory ability after CHCHD2 overexpression in H1299
and H1650 cells. (G and H) Wound-healing assays showing enhanced
migration after CHCHD2 overexpression in H1299 (G) and H1650 (H)
cells. White dashed lines indicate the wound edges used for
wound-width measurement. For the CCK-8 time-course data,
statistical significance was assessed using two-way ANOVA followed
by Sidak's multiple-comparisons test. Data are presented as the
mean ± SD. ns, not significant; *P<0.05, **P<0.01,
***P<0.001 and ****P<0.0001. CHCHD,
coiled-coil-helix-coiled-coil-helix domain; RT-qPCR, reverse
transcription-quantitative PCR; NC, negative control; CCK-8, Cell
Counting Kit-8.

Figure 6

CHCHD2 knockdown inhibits AKT/ERK
phosphorylation and suppresses lung adenocarcinoma xenograft tumor
growth. (A) Representative western blot analysis of CHCHD2, p-AKT,
t-AKT, p-ERK and t-ERK in H1975 and PC9 cells transfected with shNC
or shCHCHD2-1. GAPDH was used as the loading control. (B)
Densitometric quantification of CHCHD2 expression and the
p-AKT/t-AKT and p-ERK/t-ERK ratios in H1975 and PC9 cells. (C)
Representative images of excised xenograft tumors from the shNC and
shCHCHD2-1 groups. (D) Tumor growth curves showing xenograft tumor
volume changes over time in the shNC and shCHCHD2-1 groups. Tumor
growth curves were analyzed using repeated-measures two-way ANOVA
followed by Sidak's multiple-comparisons test. (E) Representative
IHC images of CHCHD2 staining in xenograft tumor tissues from the
shNC and shCHCHD2-1 groups. Scale bar, 100 µm. (F) Quantification
of CHCHD2 IHC staining by average optical density, showing
decreased CHCHD2 expression in the shCHCHD2-1 group. shNC,
negative-control shRNA; shCHCHD2-1, CHCHD2-targeting shRNA-1. Data
are presented as the mean ± SD. **P<0.01, ***P<0.001 and
****P<0.0001. CHCHD, coiled-coil-helix-coiled-coil-helix domain;
p-, phosphorylated; t-, total; sh-, short hairpin; NC, negative
control; IHC, immunohistochemical.
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Xu Z, Shen J, Lin Y, Shi H, Zhang C, Zhang Z, Zhou X and Yang Z: CHCHD2 as a prognostic biomarker and therapeutic target in lung adenocarcinoma: Insights from pan‑cancer multi‑omics and functional studies. Oncol Rep 56: 207, 2026.
APA
Xu, Z., Shen, J., Lin, Y., Shi, H., Zhang, C., Zhang, Z. ... Yang, Z. (2026). CHCHD2 as a prognostic biomarker and therapeutic target in lung adenocarcinoma: Insights from pan‑cancer multi‑omics and functional studies. Oncology Reports, 56, 207. https://doi.org/10.3892/or.2026.9213
MLA
Xu, Z., Shen, J., Lin, Y., Shi, H., Zhang, C., Zhang, Z., Zhou, X., Yang, Z."CHCHD2 as a prognostic biomarker and therapeutic target in lung adenocarcinoma: Insights from pan‑cancer multi‑omics and functional studies". Oncology Reports 56.6 (2026): 207.
Chicago
Xu, Z., Shen, J., Lin, Y., Shi, H., Zhang, C., Zhang, Z., Zhou, X., Yang, Z."CHCHD2 as a prognostic biomarker and therapeutic target in lung adenocarcinoma: Insights from pan‑cancer multi‑omics and functional studies". Oncology Reports 56, no. 6 (2026): 207. https://doi.org/10.3892/or.2026.9213
Copy and paste a formatted citation
x
Spandidos Publications style
Xu Z, Shen J, Lin Y, Shi H, Zhang C, Zhang Z, Zhou X and Yang Z: CHCHD2 as a prognostic biomarker and therapeutic target in lung adenocarcinoma: Insights from pan‑cancer multi‑omics and functional studies. Oncol Rep 56: 207, 2026.
APA
Xu, Z., Shen, J., Lin, Y., Shi, H., Zhang, C., Zhang, Z. ... Yang, Z. (2026). CHCHD2 as a prognostic biomarker and therapeutic target in lung adenocarcinoma: Insights from pan‑cancer multi‑omics and functional studies. Oncology Reports, 56, 207. https://doi.org/10.3892/or.2026.9213
MLA
Xu, Z., Shen, J., Lin, Y., Shi, H., Zhang, C., Zhang, Z., Zhou, X., Yang, Z."CHCHD2 as a prognostic biomarker and therapeutic target in lung adenocarcinoma: Insights from pan‑cancer multi‑omics and functional studies". Oncology Reports 56.6 (2026): 207.
Chicago
Xu, Z., Shen, J., Lin, Y., Shi, H., Zhang, C., Zhang, Z., Zhou, X., Yang, Z."CHCHD2 as a prognostic biomarker and therapeutic target in lung adenocarcinoma: Insights from pan‑cancer multi‑omics and functional studies". Oncology Reports 56, no. 6 (2026): 207. https://doi.org/10.3892/or.2026.9213
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