Introduction
Model | Type of study/country/age/FU time | Number of CVD/number of cancer in CVD | Primary outcome | Interpretation | Refs. |
---|---|---|---|---|---|
HF | Retrospective cohort/Italy/mean 76/median 5.6 yr | 103,421/12,036 | HR 1.76 (95% CI 1.71–1.81) unadjusted | HF was associated with an increased risk of cancer | [10] |
HF | Case–control/US/mean 73 yr/mean 7.7 yr | 596/102 | HR 1.60 (95% CI 1.14–2.26) adjusted for BMI, smoking, and Charlson comorbidity index | HF was associated with an increased risk of cancer | [6] |
HF (LVEF < 45%) | Prospective cohort/Denmark/mean 67.8 yr/mean 4.5 yr | 9307/975 | IRR 1.24 (95% CI 1.15–1.33) adjusted for age and sex | HF was associated with an increased risk of cancer | [7] |
HF | Retrospective cohort/Germany/mean 72.6 yr/0–10 yr | 100,124/25,732 | OR 1.76 (95% CI 1.71–1.81) unadjusted | HF was associated with an increased risk of cancer | [11] |
HF post-MI | Prospective cohort/US/mean 72 yr/mean 4.9 yr | 228/28 | HR 2.16 (95% CI 1.39–3.35) adjusted for age, sex, and Charlson comorbidity index | Post MI patients who developed HF had increased risk of cancer | [5] |
HF | Retrospective cohort/US/mean 61 yr/median 19.9 yr | 1420/177 | HR 1.02 (95% CI 0.84–1.25) adjusted for enrollment group, race, smoking, alcohol use, aspirin, family history of cancer, cirrhosis, PPI, H2 blocker, and sun exposure | HF was not associated with an increased risk of cancer among male physicians | [14] |
MI | Prospective cohort/Norway/mean 62 yr/median 15.7 yr | 1747/146 | HR 1.46 (95% CI 1.21–1.77) adjusted for age, sex, BMI, SBP, DM, HDL, smoking, physical activity, and education level | MI was associated with an increased risk of cancer | [9] |
MI | Retrospective cohort/Denmark/median male 59.2 yr, female 68.5 yr/0–17 yr | 122,275/9769 | IRR 1.08 (95% CI 1.03–1.13) adjusted for age, sex, calendar year, HT, DLP, DM, COPD, and socioeconomic status | MI was associated with an increased risk of cancer | [12] |
MI | Retrospective cohort/Denmark/median male 63 yr, female 69 yr mean 5.9 yr | 96,891/10,514 | SIR 1.05 (95% CI 1.03–1.07) unadjusted | MI was associated with an increased risk of cancer | [13] |
Potential mechanisms of the effect of CVD on the enhancement of tumor proliferation and invasiveness: Evidence from in vitro and in vivo studies
Effects of MI on tumor growth and metastases
Model | Cardiac changes | Plasma biomarker changes | Tumor status | Interpretation | Refs. | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|
LV function | LVH | Fibrosis | mRNA expression | Protein and immune | Cancer type | Growth | Metastasis | mRNA expression and immune | |||
MI-induced HF APCmin mice | ↓ | ↑ | ↑ | ↑SerpinA3, SerpinA1, FN, CP, PON1, CTGF | – | Colon | ↑ | – | – | HF enhanced colon cancer growth irrespective of hemodynamics through cardiac excreted factors | [16] |
Heterotopic heart transplant of MI heart in APCmin mice into APCmin mice | ↔ | ↑ | ↑ | ↑SerpinA3, FN, PON1 ↔ SerpinA1, CP | – | Colon | ↑ | – | – | ||
MI-induced HF mice with xenograft LLC | ↓ | – | – | ↑miR-22-3p, pre-mi-R-22 | ↑miR-22-3p | Lung | ↑↑ | – | ↑miR-22-3p ↔pre-mi-R-22 | MI-induced HF enhanced tumor growth by attenuation of tumor sensitivity to ferroptosis via miR-22-3p | [18] |
MI-induced HF mice with xenograft LLC + erastin 30 mg/kg/IP/OD | ↓ | – | – | – | – | Lung | ↑ | – | – | ||
MI-induced HF mice with xenograft LLC + IKE 30 mg/kg/IP/OD | ↓ | – | – | – | – | Lung | ↑ | – | – | ||
Xenograft LLC mice + erastin 30 mg/kg/IP/OD | ↔ | – | – | – | – | Lung | ↓↓ | – | – | ||
Xenograft LLC mice + erastin 30 mg/kg/IP/OD + Sham-EXO/Intra-tumor/q 48 h | ↔ | – | – | – | – | Lung | ↓↓ | – | – | ||
Xenograft LLC mice + erastin 30 mg/kg/IP/OD + Sham-EXO/Intra-tumor/q 48 h | ↓ | – | – | – | – | Lung | ↓ | – | – | ||
MI-induced HF in inhibited cardiomyocyte specific miR-22-3p mice with xenograft LLC + erastin 30 mg/kg/IP/OD | ↓ | – | – | ↓ miR-22-3p | ↓ miR-22-3p | Lung | ↓ | – | ↓ miR-22-3p | ||
TAC-induced pressure overload mice with orthotopic breast cancer (PyMT) | ↓ | ↑ | ↔ | ↑periostin, CTGF | ↑periostin, CTGF ↔CD8+ T cell | Breast | ↑ | ↔ | ↔CD8+ T cell | Early cardiac remodeling increased breast and lung cancer growth and metastasis possibly via periostin and CTGF | [23] |
TAC-induced pressure overload mice + PyMT injection | ↓ | ↑ | ↔ | ↑periostin, CTGF | ↑periostin, CTGF | Breast | – | ↑ | – | ||
TAC-induced pressure overload mice with xenograft lung cancer (LLC) | ↓ | ↑ | ↔ | ↑periostin, CTGF | ↑periostin, CTGF ↔CD8+ T cell | Lung | ↑ | ↔ | ↔CD8+ T cell | ||
TAC-induced pressure overload mice + LLC injection | ↓ | ↑ | ↔ | ↑periostin, CTGF | ↑periostin, CTGF | Lung | – | ↑ | – | ||
TAC-induced pressure overload NOD/SCID mice with orthotopic breast cancer | ↓ | ↑ | ↔ | ↑periostin, CTGF | ↑periostin, CTGF | Breast | ↑ | – | – | ||
TAC-induced pressure overload MCRR mice with orthotopic breast cancer | ↔ | ↔ | – | ↔periostin, CTGF | ↔periostin, CTGF | Breast | ↔ | – | – | ||
Low-dose PE induced hypertension mice with orthotopic breast cancer (PyMT) | ↔ | ↑ | ↑ | ↑periostin, FN ↔CTGF, SerpinA3, SerpinE1, PON1, CP | ↑periostin, FN, CTGF | Breast | ↑ | – | ↑CTGF ↔periostin, FN, SerpinA3, SerpinE1, PON1, CP | Cardiac remodeling in the absence of contractile dysfunction was sufficient to promote breast cancer growth | [25] |
ATF3-transgenic mice with orthotopic breast cancer (PyMT) | ↓ | ↑ | ↑ | ↑periostin, SerpinA3, SerpinE1, CP, CTGF, FN | ↔CP, CTGF, FN | Breast | ↑ | – | ↑CTGF, FN ↔SerpinA3 | Cardiac remodeling promoted tumor growth in ATF3-transgenic mice with breast and lung cancer models | [24] |
ATF3-transgenic mice + PyMT injection | – | – | – | – | – | Breast | – | ↑ | – | ||
ATF3-transgenic mice with xenograft LLC | ↓ | ↑ | – | – | – | Lung | ↑ | – | – | ||
ATF3-transgenic mice with orthotopic breast cancer + doxycycline | – | ↑ | – | – | – | Breast | ↑ | – | – | ||
ATF3-transgenic mice + doxycycline + PyMT injection | – | – | – | – | – | Breast | – | ↑ | – | ||
MI-induced mice with orthotopic breast cancer (E0771) | ↓ | ↑ | – | – | ↑Ly6Chi monocyte | Breast | ↑ | – | ↑Ly6Chi monocyte ↓T cells ↑Treg cells | MI enhanced tumor growth in breast cancer mice model via reprogramming of myeloid cells toward immunosuppressive state | [17] |
CD45.2 mice implanted E0771 tumor + isolated Ly6Chi monocytes from MI-induced CD45.1 non-tumor bearing mice | – | – | – | – | – | Breast | ↔ | – | ↔Ly6Chi CD45.1 | ||
MI-induced CD45.2 mice implanted E0771 tumor + isolated Ly6Chi monocytes from naive CD45.1 non-tumor bearing mice | – | – | – | – | – | Breast | ↔ | – | ↑Ly6Chi CD45.1 | ||
MI-induced CCR2DTR mice implanted E0771 tumor + DT injection (vs MI WT) | – | – | – | – | ↓Ly6Chi monocyte | Breast | ↓ | – | ↓Ly6Chi monocytes ↓Treg cells ↑CD8+ T cell ↑CD8+GrB+ | ||
Sham-operated CCR2DTR mice implanted E0771 tumor + DT injection | – | – | – | – | ↓Ly6Chi monocyte | Breast | ↔ | – | ↓Ly6Chi monocytes ↔ Treg cells ↑CD8+ T cell ↔ CD8+GrB+ | ||
MI-induced mice implanted E0771 tumor + anti-CD8 | – | – | – | – | – | Breast | ↔ | – | ↓T cells | ||
Sham-operated mice implanted E0771 tumor + anti-CD8 | – | – | – | – | – | Breast | ↔ | – | ↓T cells | ||
CD45.1 mice + BM transplant from MI-induced CD45.2 mice implanted E0771 tumor + implanted E0771 after BM transplant (vs sham) | – | – | – | – | ↑Ly6Chi monocytes | Breast | ↑ | – | – | ||
MI-induced MMTV-PyMT mice | – | – | – | – | – | Breast | ↑ | ↑ | ↑Ly6Chi monocytes ↔ T cells ↔ Treg cells | ||
MI-induced HF mice with orthotopic renal cancer (Renca cells) | ↓ | ↑ | ↑ | – | – | Renal | ↔ | ↔ | – | HF had neutral effect on renal cancer cell growth in MI-induced HF mice model | [19] |
Model | Exposure | Proliferation | Invasion/migration | Interpretation | Refs. |
---|---|---|---|---|---|
Colon cancer cells (HT-29) | SerpinA3/10 ng/mL | ↑ | – | SerpinA3 and SerpinA1 promoted colon cancer cell proliferation | [16] |
SerpinA1/50 ng/mL | ↑ | – | |||
Fibronectin/20 mcg/mL | ↔ | – | |||
Paraoxonase 1/10 mM | ↔ | – | |||
Ceruloplasmin 0.1 mcM | ↔ | – | |||
Breast cancer cells (PyMT) | Serum of TAC-operated mice with PyMT model/48 h | ↑↑ | – | Periostin was increased in early cardiac remodeling in TAC mice and promoted breast and lung cancer cell proliferation | [23] |
Serum from TAC-operated mice without cancer/48 h | ↑ | – | |||
Periostin 2000–4000 ng/mL/48 h | ↑ | – | |||
Periostin 1000 ng/mL/48 h | ↔ | – | |||
Periostin-depleted serum of TAC-operated mice with PyMT model/48 h | ↔ | – | |||
Lung cancer cells (LLC) | Serum from TAC-operated mice with LLC model/48 h | ↑ | – | ||
Serum from TAC mice-operated mice without cancer/48 h | ↑ | – | |||
Periostin 2000–4000 ng/mL/48 h | ↑ | – | |||
Periostin 1000 ng/mL/48 h | ↔ | – | |||
PyMT cells | Serum from low-dose PE-infused mice/48 h | ↑ | – | Serum derived from PE-induced cardiac remodeling mice enhanced breast cancer cell proliferation | [25] |
PyMT cells | Serum from AFT-3 transgenic mice/48 h | ↑ | – | Cardiac remodeling in AFT-3 transgenic mice without pressure overload increased breast and lung cancer cells growth and invasiveness | [24] |
Serum from AFT-3 transgenic mice + doxycycline/48 h | ↑ | – | |||
LLC cells | Serum from AFT-3 transgenic mice/48 h | ↑ | – | ||
LLC cells | Erastin/20 mcM/24 h | ↓↓ | ↓↓ | MI-derived EXO attenuated lung cancer and osteosarcoma cells | [18] |
Erastin/20 mcM/24 h + Sham-EXO 1 mcg/mL/24 h | ↓↓ | ↓↓ | |||
Erastin/20 mcM/24 h + MI-EXO 1 mcg/mL/24 h | ↓ | ↓ | |||
Osteosarcoma cells (K7M2) | Erastin/5 mcM/24 h | ↓↓ | ↓↓ | ||
Erastin/5 mcM/24 h + Sham-EXO 1 mcg/mL/24 h | ↓↓ | ↓↓ | |||
Erastin/5 mcM/24 h + MI-EXO 1 mcg/mL/24 h | ↓ | ↓ | |||
LLC cells | Erastin/20 mcM/24 h | – | ↓↓↓ | MI-derived EXO further enhanced antiferroptotic activity of Fer-1 in erastin-induced suppression of invasion and migration | |
Erastin/20 mcM/24 h + Fer-1 2 mcM/24 h | – | ↓↓ | |||
Erastin/20 mcM/24 h + Fer-1 2 mcM/24 h + Sham-EXO 1 mcg/mL/24 h | – | ↓↓ | |||
Erastin/20 mcM/24 h + Fer-1 2 mcM/24 h + MI-EXO 1 mcg/mL/24 h | – | ↓ | |||
LLC cells | miR-22-3p mimics | ↔ | – | miR-22-3p attenuated erastin-induced ferroptosis | |
Erastin/20 mcM/24 h | ↓↓ | – | |||
Erastin/20 mcM/24 h + miR-22-3p mimics | ↓ | – | |||
AMO-22-3p | ↔ | – | |||
Erastin/20 mcM/24 h | ↓↓ | – | |||
Erastin/20 mcM/24 h + AMO-22-3p | ↓↓↓ | – |
Cardiac hypertrophy
Potential cardiokines and mi-RNAs as potential links between CVD and cancer
Potential cardiokines and miR | Model | Cardiac expression | Plasma level | LV function | LVH | Outcome | Interpretation | Refs. |
---|---|---|---|---|---|---|---|---|
SerpinA3 | In vitro study | |||||||
HASMCs + ox-LDL 100mcg/mL/12 h | ↑ | – | – | – | – | Cardiac SerpinA3 expression was increased in aortic smooth muscle cells in atherosclerosis model | [27] | |
In vivo studies | ||||||||
MI-induced HF APCmin mice | ↑ | – | ↓ | ↑ | – | Cardiac SerpinA3 expression was increased in MI-induced HF mice model | [16] | |
Heterotopic heart transplant of MI heart in APCmin mice into APCmin mice | ↑ | – | ↔ | ↑ | – | |||
ATF3-transgenic mice | ↑ | – | ↓ | ↑ | – | Cardiac SerpinA3 expression was increased in cardiac remodeling model using ATF3-transgenic mice | [24] | |
Low-dose PE induced hypertension mice | ↔ | – | ↔ | ↑ | – | Cardiac SerpinA3 expression was not changed in cardiac remodeling without LV systolic dysfunction | [25] | |
Clinical studies | ||||||||
CAD patients | – | ↑ | ↔ | – | – | Plasma SerpinA3 level was elevated in CAD patients and correlated with extension of coronary artery atherosclerosis | [27] | |
MI patients | – | ↑ | ↔ | – | ↑MACE | Plasma SerpinA3 level was elevated in MI patients, and was a predictor of MACE | [28] | |
DCM patients | ↑ | ↑ | ↓ | – | ↓survival | Plasma and cardiac SerpinA3 levels were elevated in DCM and associated with poor outcome in DCM patients | [29] | |
HFrEF patients | – | ↑ | ↓ | – | ↔survival | Plasma SerpinA3 level was elevated in HFrEF patients | [30] | |
DCM patients pre LVAD implantation | ↔ | ↑ | ↓ | – | – | Plasma SerpinA3 level was elevated in HF patients and decreased after LVAD implantation | [31] | |
DCM patients post LVAD implantation | ↓ | ↔ | – | – | – | |||
Calcific AS patients | ↑ | ↑ | – | – | – | Plasma and cardiac SerpinA3 levels were elevated in calcific AS | [32] | |
SerpinA1 | In vivo study | |||||||
MI-induced HF APCmin mice | ↑ | – | ↓ | ↑ | – | Cardiac SerpinA1 expression was increased in MI-induced HF mice | [16] | |
Heterotopic heart transplant of MI heart in APCmin mice into APCmin mice | ↔ | – | ↔ | ↑ | – | |||
Clinical studies | ||||||||
MI patients | – | ↑ | – | – | ↑survival | Plasma SerpinA1 level was elevated in MI patients, and was associated with improved prognosis | [39] | |
HFrEF patients | – | ↑ | ↓ | – | ↑NYHA | Plasma SerpinA1 level was increased in HFrEF patients, and was associated with higher NYHA class | [40] | |
Periostin | In vitro study | |||||||
Adult rat cardiac fibroblasts + Ang II/10–7–10–5 M/24–48 h | ↑ | – | – | – | – | Ang II enhanced periostin expression in adult rat cardiac fibroblasts | [47] | |
In vivo studies | ||||||||
MI mice | ↑ | – | – | – | – | Cardiac periostin expression was increased in MI mice | ||
Chronic Ang II-induced HT mice | ↑ | – | – | ↑ | – | Cardiac periostin expression was increased in chronic Ang II-induced LVH in mice | [47] | |
High salt-induced HT rat | ↑ | – | – | – | – | Cardiac periostin expression was increased in high salt-induced HT rat model | [48] | |
Aortic banding-induced HF mice | ↑ | – | ↓ | ↑ | – | Cardiac periostin expression was increased in hypertensive-induced cardiac remodeling | [52] | |
Clinical studies | ||||||||
MI patients | ↑ | – | – | – | – | Cardiac periostin expression was increased in MI patients | [49] | |
STEMI patients | – | ↑ (vs lower group) | – | – | ↓LVEF ↑CV events | Elevated plasma periostin level was associated with LVEF decline and increased CV events in STEMI patients | [54] | |
HFrEF patients | ↑ | – | ↓ | – | – | Cardiac periostin expression was increased in HFrEF patients | [53] | |
HFrEF patients on LVADs | ↑ (vs off LVADs) | – | ↓ | – | – | Cardiac periostin expression was decreased after offload of LVADs in HFrEF patients | [52] | |
miR-21 | In vitro study | |||||||
Neonatal rat cardiomyocytes + PE/100 mcM | ↑ | – | – | – | – | miR-21 expression was increased in hypertrophic stimulated rat cardiomyocytes | ||
Neonatal rat cardiomyocytes + LIF/1000 units/ml | ↑ | – | – | – | – | |||
Neonatal rat cardiomyocytes + FBS/10% | ↑ | – | – | – | – | |||
Neonatal rat cardiomyocytes + Ang II/1 mcM/48 h | ↑ | – | – | – | – | miR-21 expression was increased in Ang II-induced hypertrophy rat cardiomyocytes | [69] | |
In vivo studies | ||||||||
Cardiac I/R mice | ↑ | – | – | – | – | Cardiac miR-21 expression was increased in a cardiac I/R mice model | [71] | |
MI rat | ↑ (border) ↓ (infarct) | – | – | – | – | Cardiac miR-21 expression was increased at border zone and decreased at infarct zone in MI rat model | [72] | |
MI mice | ↑ | – | – | ↑ | – | Cardiac miR-21 expression was increased at infarct zone in MI mice model | [73] | |
Thoracic aortic banding-induced cardiac hypertrophy mice | ↑ | – | – | ↑ | – | Cardiac miR-21expression was increased in cardiac hypertrophy mice | ||
β1-adrenergic receptor transgenic mice with HF | ↑ | – | ↓ | – | – | Cardiac miR-21 expression was increased in HF mice | [70] | |
TAC-induced HF mice | ↑ | – | ↓ | ↑ | – | |||
Isoproterenol-induced HF mice | ↑ | – | ↓ | ↑ | – | |||
Clinical studies | ||||||||
ACS patients | – | ↑ | – | – | – | Plasma miR-21 level was increased in ACS patients | [75] | |
CAD patients | – | ↑ | – | – | – | Plasma miR-21 level was increased in CAD patients | [75] | |
HFrEF patients | – | ↑ | ↓ | – | ↓LVEF ↑NYHA | Plasma miR-21 level was increased in HFrEF patients and associated with decreased LVEF and increased NYHA | [74] | |
HFrEF patients | ↑ | – | ↓ | – | – | Cardiac miR-21 expression was increased in HFrEF patients | [70] | |
miR-22 | In vitro studies | |||||||
Neonatal rat cardiomyocytes + PE + FBS | ↑ | – | – | – | – | miR-22 expression increased in PE-induced cardiomyocyte hypertrophy | [94] | |
Neonatal rat cardiomyocytes + Ang II/1 mcM/48 h | ↑ | – | – | – | – | miR-22 expression was increased in Ang II-induced hypertrophy rat cardiomyocytes | [69] | |
In vivo studies | ||||||||
MI mice | ↑ | ↑ | ↓ | – | – | Cardiac expression and plasma level of miR-22-3p were increased in MI nice model | [18] | |
TAC-induced cardiac hypertrophy mice | ↑ | – | – | ↑ | – | Cardiac miR-22 expression was increased in early phase of TAC-induced cardiac hypertrophy mice | [94] | |
Clinical studies | ||||||||
HFrEF patients | ↑ | – | ↓ | – | – | Cardiac miR-22 expression was increased in HFrEF patients | [95] | |
HFrEF patients | – | ↑ | ↓ | – | ↑CV death | Plasma miR-22 level was increased in HFrEF patients and associated with CV death | [96] | |
HF patients | – | ↑ (vs lower group) | – | – | ↓CV events | Higher plasma miR-22-3p level was associated with lower frequency of CV events in HF patients | [97] | |
CAD patients | – | ↑ | – | – | – | Plasma miR-22-3p level was increased in CAD patients | ||
CAD patients | – | ↓ | – | – | – | Plasma miR-22 level was increased in CAD patients | [100] |
Potential cardiokines and miR | Model | Tumor expression | Plasma level | Growth | Metastasis/invasion/migration | Survival | Interpretation | Refs |
---|---|---|---|---|---|---|---|---|
Serpin A3 | In vitro studies | |||||||
Colon cancer cells (HT-29) + SerpinA3/10 ng/mL | – | – | ↑ | – | – | SerpinA3 enhanced colon cancer cell proliferation | [16] | |
Colon cancer cells with high metastatic potential (HT-29LMM, KM-12L4) | ↑ (vs low metastatic) | – | – | – | – | SerpinA3 expression was higher in colon cancer cells with higher metastatic potential and associated with colon cancer cell migration and invasion | [34] | |
HT-29LMM, KM-12L4 + downregulated SerpinA3 | ↓ | – | – | ↓ | – | |||
Breast cancer cells (MDA-MB-231, BT549, MCF-7, T-47D) + upregulated SerpinA3 | ↑ | – | ↑ | ↑ | – | SerpinA3 enhanced breast cancer cell invasion and migration | [35] | |
MDA-MB-436 + downregulated SerpinA3 | ↓ | – | ↓ | ↓ | – | |||
Lung adenocarcinoma cells (CADO-LC11, LC29, LC45) | ↑ | – | – | – | – | SerpinA3 expression was increased in lung adenocarcinoma cells | [33] | |
Lung non-adenocarcinoma cells (OC-35, OC-10, CADO-LC22, CADO-LC3, CADO-LC15) | ↔ | – | – | – | – | |||
GBM cells (U251MG) + downregulated SerpinA3 | ↓ | – | – | ↓ | – | SerpinA3 enhanced GBM cell invasion | [36] | |
In vivo studies | ||||||||
MI-induced HF APCmin mice | – | – | ↑ | – | – | Increased SerpinA3 cardiac expression in MI-induced HF was associated with increased tumor growth in APCmin mice model | [16] | |
Heterotopic heart transplant of MI heart in APCmin mice into APCmin mice | – | – | ↑ | – | – | |||
ATF3-transgenic mice with PyMT | ↔ | – | ↑ | – | – | Cardiac remodeling in ATF3-transgenic mice did not increase SerpinA3 expression, but enhanced breast cancer growth | [24] | |
Low-dose PE induced hypertension mice with PyMT | ↔ | – | ↑ | – | – | Cardiac remodeling without LV systolic dysfunction did not increase Serpin A3 expression, but enhanced breast cancer growth | [25] | |
Mice + downregulated SerpinA3 colon cancer cells (HT-29LMM) | ↓ | – | – | ↓ | – | SerpinA3 regulated liver metastasis of colon cancer in a mouse model | [34] | |
Clinical studies | ||||||||
Colon cancer patients | ↑ (vs negative) | – | ↔ | ↑ | – | Increased SerpinA3 expression in colon cancer tissue was associated with metastasis | [34] | |
Lung cancer patients | ↑ (vs negative) | – | ↑ | ↔ | ↓ | Increased SerpinA3 expression in lung cancer tissue was associated with larger tumor size and poor survival | [33] | |
Lung cancer patients | – | ↑ | – | ↑ | – | Plasma SerpinA3 levels was increased in lung cancer patients and associated with metastasis | [38] | |
Breast cancer patients | ↑ | – | – | – | – | SerpinA3 expression was increased in breast cancer tissue | [35] | |
Glioma patients | ↑ | – | – | – | ↓ | SerpinA3 expression was increased in brain glioma tissue and associated with poor survival | [36] | |
Serpin A1 | In vitro studies | |||||||
Colon cancer cells (HT-29) + SerpinA1/50 ng/mL | – | – | ↑ | – | – | SerpinA1 enhanced colon cancer cell proliferation | [16] | |
Gastric cancer cells (AGS, MKN45) + upregulated SerpinA1 | ↑ | – | – | ↑ | – | SerpinA1 promoted gastric cancer cell migration and invasion | [44] | |
AGS, MKN45 + downregulated SerpinA1 | ↓ | – | – | ↓ | – | |||
Colon cancer cells (DLD-1, SW-480) + upregulated SerpinA1 | ↑ | – | – | ↑ | – | SerpinA1 promoted colon, breast and ovarian cancer cell invasion and migration | [42] | |
DLD-1, SW-480 + downregulated SerpinA1 | ↓ | – | – | ↓ | – | |||
Breast cancer cell (MCF-7, MDA-MB-231) + upregulated SerpinA1 | ↑ | – | – | ↑ | – | |||
MCF-7, MDA-MB-231 + downregulated SerpinA1 | ↓ | – | – | ↓ | – | |||
Ovarian cancer cells (A2780, SKVO3) + upregulated SerpinA1 | ↑ | – | – | ↑ | – | |||
A2780, SKVO3 + downregulated SerpinA1 | ↓ | – | – | ↓ | – | |||
Lung adenocarcinoma cell with high metastatic potential (CL1-5) | ↑ (vs low metastatic CL1-0) | – | – | – | – | SerpinA1 expression was higher in lung adenocarcinoma cells with higher metastatic potential and associated with cell migration and invasion | [43] | |
CL1-5 + downregulated SerpinA1 | ↓ | – | – | ↓ | – | |||
CL1-0 + upregulated SerpinA1 | ↑ | – | – | ↑ | – | |||
Lung adenocarcinoma cells (A549, SPC-A1) + upregulated SerpinA1 | ↑ | – | – | ↑ | – | SerpinA1 promoted lung cancer cell migration | [45] | |
A549, SPC-A1 + downregulated SerpinA1 | ↓ | – | – | ↓ | – | |||
NSCLC cells (H661) + upregulated SerpinA1 | ↑ | – | ↑ | ↑ | – | SerpinA1 promoted NSCLC cell proliferation and migration | [41] | |
NSCLC cells (H1975) + downregulated SerpinA1 | ↓ | – | ↓ | ↓ | – | |||
In vivo study | ||||||||
Mice + lung adenocarcinoma cells (CL1-5) | ↑ | – | – | ↑ | – | SerpinA1 promoted lung metastasis in lung adenocarcinoma mice | [43] | |
Mice + downregulated SerpinA1 CL1-5 | ↓ | – | – | ↔ | – | |||
Clinical studies | ||||||||
Gastric cancer patients | ↑ (vs negative) | – | ↑ | ↑ | ↓ | SerpinA1 expression was associated with tumor size, lymph node metastasis and poor survival in gastric cancer patients | [44] | |
Colorectal cancer patients | ↑ (vs negative) | – | ↑ | ↑ | ↓ | SerpinA1 expression was associated with tumor size, metastasis and poor survival in colorectal cancer patients | [42] | |
Lung adenocarcinoma patients | ↑(vs negative) | – | ↔ | ↑ | ↓ | SerpinA1 expression was associated with lymph node metastasis and poor survival in lung adenocarcinoma patients | ||
NSCLC patients | ↓ | – | – | – | ↓ | SerpinA1 expression was decreased in NSCLC tumor tissue and was associated with poor survival | [41] | |
Periostin | In vitro studies | |||||||
Breast cancer cells (PyMT) + Periostin 2000–4000 ng/mL/48 h | – | – | ↑ | – | – | Periostin enhanced breast and lung cancer cell proliferation | [23] | |
PyMT + Periostin 1000 ng/mL/48 h | – | – | ↔ | – | – | |||
Lung cancer cells (LLC) + Periostin 2000–4000 ng/mL/48 h | – | – | ↑ | – | – | |||
LLC + Periostin 1000 ng/mL/48 h | – | – | ↔ | – | – | |||
Colon cancer cells (CX-1NS) in serum depleted condition + upregulated periostin | ↑ | – | – | – | – | Periostin promoted colon cancer cell survival in conditions of stress | [58] | |
Breast cancer cells (MCF-7) + upregulated periostin | ↑ | – | – | – | – | Periostin promoted angiogenesis in breast cancer cells | [57] | |
NSCLC cells (A549) + upregulated periostin | ↑ | – | ↑ | ↑ | – | Periostin enhanced NSCLC cell proliferation and migration | [56] | |
In vivo studies | ||||||||
Mice + upregulated periostin colon cancer cells (CX-1NS) | ↑ | – | – | ↑ | – | Periostin enhanced colon cancer growth and metastasis in mouse model | [58] | |
SCID mice + upregulated periostin breast cancer cells (MDA-MB-231) | ↑ | – | ↑ | – | – | Periostin enhanced breast cancer growth in an SCID mouse model | [57] | |
Clinical studies | ||||||||
Colon cancer patients | ↑ | ↑ | – | ↑ | ↓ | Plasma periostin and tumor expression were increased in colon cancer and associated with metastasis and poor survival | ||
Breast cancer patients | ↑ | – | ↔ | ↔ | ↓ | Tumor periostin expression was increased in breast cancer and associated with poor survival | ||
Breast cancer patients | – | ↑ | ↔ | ↑ | – | Plasma periostin level was higher in breast cancer with bone metastasis | [66] | |
NSCLC patients | ↑ | ↑ | ↔ | ↔ | ↓ | Plasma periostin level and tumor expression were elevated in NSCLC patients and associated with poor survival | ||
HCC patients | ↑ (vs low level) | – | ↔ | ↑ | ↓ | Higher periostin expression in HCC was associated with metastasis and poor survival | [62] | |
HCC patients | – | ↑ | ↔ | ↔ | ↓ | Plasma periostin level was increased in HCC patients and associated with poor survival | [65] | |
Prostate cancer patients | ↑ | – | – | ↑ | ↓ | Tumor periostin expression was increased in prostate cancer and associated with advanced stages and poor survival | ||
miR-21 | In vitro studies | |||||||
Colorectal cancer cells (HCT-116, SW480) + upregulated miR-21 | ↑ | – | ↑ | ↑ | – | miR-21 promoted colorectal cancer cell proliferation and invasion | [78] | |
HCT-116, SW480 + downregulated miR-21 | ↓ | – | ↓ | ↓ | – | |||
Colorectal cancer cells (RKO) + downregulated miR-21 | ↓ | – | – | ↓ | – | miR-21 promoted colorectal cancer cell invasion and metastasis | [81] | |
Breast cancer cells (BCAP-37, MCF-7, MDA-MB-231, MDA-MB-435) | ↑ | – | – | – | – | miR-21 increased expression in breast cancer cells and associated with cancer invasiveness | [82] | |
MDA-231 + upregulated miR-21 | ↑ | – | – | ↑ | – | |||
MDA-231 + downregulated miR-21 | ↓ | – | – | ↓ | – | |||
MDA-435 + downregulated miR-21 | ↓ | – | – | ↓ | – | |||
MCF-7 + upregulated miR-21 | ↑ | – | – | ↑ | – | miR-21 promoted breast cancer cell invasion and migration | [83] | |
NSCLC cells (H2170, A549, SPC-A1) | ↑ | – | – | – | – | miR-21 expression was increased in NSCLC cells and associated with proliferation, migration and invasion | [79] | |
A549, H2170 + upregulated miR-21 | ↑ | – | ↑ | ↑ | – | |||
A549, H2170 + downregulated miR-21 | ↓ | – | ↓ | ↓ | – | |||
Gastric cancer cells (BGC-823) + upregulated miR-21 | ↑ | – | ↑ | ↑ | – | miR-21 promoted gastric cancer cell growth and invasion | [80] | |
BGC-823 + downregulated miR-21 | ↓ | – | ↓ | ↓ | – | |||
Glioblastoma cells (A172, U87, U373, LN229, LN428, LN308) | ↑ | – | – | – | – | miR-21 expression was increased in glioblastoma cell lines | [84] | |
Glioblastoma cells (A172, U87) + downregulated miR-21 | ↓ | – | – | ↓ | – | miR-21 enhanced glioblastoma cell invasion | [85] | |
HCC cells (HepG2, SK-HEP-1, SNU182, SNU449, PLC/PRF-5) | ↑ | – | – | ↑ | – | miR-21 expression was increased in HCC cells and associated with invasiveness | [86] | |
HepG2, SK-HEP-1, SNU182, PLC/PRF-5 + downregulated miR-21 | ↓ | – | – | ↓ | – | |||
DLBCL cells (CRL-2630) | ↑ | – | – | – | – | miR-21 expression was increased in DLBCL cells | [87] | |
In vivo studies | ||||||||
Mice + upregulated miR-21 colon cancer cells (HCT-116) | ↑ | – | ↑ | – | – | miR-21 promoted colorectal cancer growth in mouse model | [78] | |
Mice + downregulated miR-21 HCT-116 | ↓ | – | ↓ | – | – | |||
Mice + downregulated miR-21 breast cancer cells (MCF-7) | ↓ | – | ↓ | – | – | miR-21 promoted breast cancer growth in mouse model | [83] | |
Clinical studies | ||||||||
Colorectal cancer patients | ↑ | – | – | ↑ | – | miR-21 expression was increased in colorectal cancer and associated with metastasis | [78] | |
Colon cancer patients | ↑ | – | – | – | ↓ | miR-21 expression was increased in colon cancer and associated with poor survival in colon cancer patients | [89] | |
Breast cancer patients | ↑ | – | – | ↑ | – | miR-21 expression was increased in breast cancer and associated with metastasis | ||
Breast cancer patients | – | ↑ | – | – | – | Plasma miR-21 levels were increased in breast cancer patients | [83] | |
NSCLC patients | – | ↑ | – | ↑ | ↓ | Plasma miR-21 level was increased in NSCLC patients and associated with lymph node metastasis and poor survival | [90] | |
NSCLC patients | ↑ | – | – | ↑ | – | Tumor miR-21 expression was increased in NSCLC and associated with lymph node metastasis | [79] | |
Lung cancer patients | ↑ | – | – | – | – | Tumor miR-21 expression was increased in lung cancer tissue | [88] | |
Prostate cancer patients | ↑ | – | – | – | – | Tumor miR-21 expression was increased in prostate cancer tissue | [88] | |
Prostate cancer patients | – | ↑ | – | ↑ | – | Plasma miR-21 level was increased in prostate cancer patients and associated with metastasis | [92] | |
Gastric cancer patients | – | ↑ | – | – | – | Plasma miR-21 level was increased in gastric cancer patients | [91] | |
Gastric cancer patients | ↑ | – | – | ↑ | – | Tumor miR-21 expression was increased in gastric cancer and associated with lymph node metastasis | [80] | |
Glioma patients | ↑ | – | – | – | – | Tumor miR-21 expression was increased in glioma | [85] | |
HCC patients | ↑ | – | – | – | – | Tumor miR-21 expression was increased in HCC | [86] | |
DLBCL patients | ↑ | – | – | – | – | Tumor miR-21 expression was increased in DLBCL | [87] | |
miR-22 | In vitro studies | |||||||
NSCLC cells (A549, H1299) | ↓ | – | – | – | – | miR-22 expression was decreased in NSCLC cell lines and suppressed cancer cell proliferation and migration | [102] | |
A549, H1299 + Overexpressed miR-22 | ↑ | – | ↓ | ↓ | – | |||
NSCLC cells (H1975, H1299) + transfected miR-22-3p | ↑ | – | ↓ | – | – | miR-22-3p inhibited NSCLC cell proliferation | [105] | |
H1975, H1299 + miR-22-3p inhibitor | ↓ | – | ↑ | – | – | |||
Colorectal cancer cells (SW480, SW620, Caco2, HT29, LOVO, HCT15, HCT116) | ↓ | – | – | – | – | miR-22 expression was decreased in colorectal cancer cell lines and decreased proliferation and migration of colon cancer cells | [104] | |
SW480 + Overexpressed miR-22 | ↑ | – | ↓ | ↓ | – | |||
SW480 + miR-22 inhibitor | ↓ | – | ↑ | ↑ | – | |||
HCC cells (Hep3B, SMMC7721) | ↓ | – | – | – | – | miR-22 expression was decreased in HCC cell lines and suppressed tumor cell proliferation | [103] | |
Hep3B, SMMC7721 + transfected with miR-22 | ↑ | – | ↓ | – | – | |||
Triple negative breast cancer cells (MDA-MB-231, MDA-MB-436, BT-20) | ↓ | – | – | – | – | miR-22-3p expression was decreased in triple negative breast cancer cells and suppressed cell proliferation and migration | [106] | |
MDA-MB-231, MDA-MB-436 + transfected with miR-22-3p | ↑ | – | ↓ | ↓ | – | |||
Highly metastatic breast cancer cells (MDA-MB-231, Hs578T) | ↑ (vs low metastatic MCF7, T47D) | – | – | – | – | miR-22 expression was higher in highly metastatic breast cancer cell lines and increased cell migration and invasion | [107] | |
MDA-MB-231 + miR-22 inhibitor | ↓ | – | – | ↓ | – | |||
MCF7 + overexpressed miR-22 | ↑ | – | – | ↑ | – | |||
Prostate cancer cells (Ca-HpV-10, DU145, PC3, VCap) | ↑ | – | – | – | – | miR-22 expression was increased in prostate cancer cell lines | [108] | |
In vivo studies | ||||||||
Mice + Overexpressed miR-22 in NSCLC cells (A549) | ↑ | – | ↓ | – | – | miR-22 suppressed lung cancer growth in mice | [102] | |
Xenograft colorectal cancer mice + overexpressed miR-22 colorectal cancer cells (SW480) | ↑ | – | ↓ | – | – | Overexpression of miR-22 inhibited colorectal cancer growth | [104] | |
Mice + overexpressed miR-22 in HCC cells (Hep3B/SMMC7721) | ↑ | – | ↓ | – | – | miR-22 suppressed HCC growth in mice | [103] | |
Orthotopic immunodeficient mice + overexpressed miR-22 in breast cancer cells (MCF-7) | ↑ | – | – | ↑ | – | miR-22 enhanced breast cancer cell metastasis | [112] | |
MMTV-miR-22 transgenic mice | ↑ | – | ↑ | ↑ | – | miR-22 promoted breast cancer growth and distant metastasis | ||
Orthotopic breast cancer mice (MDA-MB-231, MDA-MB-436) + miR-22-3p | ↑ | – | ↓ | – | – | miR-22-3p suppressed breast cancer proliferation | [106] | |
Mice + overexpressed miR-22 in prostate cancer cells (DU145) | ↑ | – | ↑ | – | – | miR-22 promoted prostate cancer growth | [108] | |
Clinical studies | ||||||||
NSCLC patients | ↓ | – | – | – | – | Tumor miR-22-3p expression was decreased in NSCLC patients | [105] | |
Lung cancer patients | ↓ | – | – | – | – | Tumor miR-22-3p expression was decreased in lung cancer patients | [102] | |
Advanced NSCLC patients | – | ↑ | – | – | – | Plasma miR-22 level was increased in advanced NSCLC patients | [111] | |
Colorectal cancer patients | ↓ | – | – | ↓ | ↑ | Tumor miR-22 expression was decreased in colon cancer and low miR-22 expression was associated with poor survival and liver metastasis | ||
Colorectal cancer patients | – | ↓ | – | – | – | Plasma miR-22-3p level was decreased in colorectal cancer patients | [113] | |
Colon cancer patients | ↑ | – | – | – | – | Tumor miR-22-3p expression was increased in colon cancer patients | [110] | |
HCC patients | ↓ | – | – | – | ↑ | Tumor miR-22 expression was decreased in HCC and low miR-22 expression was associated with poor survival | [103] | |
Triple negative breast cancer patients | ↓ | – | – | – | – | Tumor miR-22-3p expression was decreased in triple negative breast cancer patients | [106] | |
Breast cancer patients | ↑ (vs low level) | – | – | – | ↓ | Elevated tumor miR-22 expression was associated with poor survival in breast cancer patients | [107] | |
Prostate cancer patients | ↑ | – | – | – | – | Tumor miR-22 expression was increased in prostate cancer patients | [108] | |
Pancreatic cancer patients | – | ↑ | – | – | – | Plasma miR-22-3p level was increased in pancreatic cancer patients | [114] |